BRPI0617100A2 - pyridazinone derivative compound, pharmaceutical composition, method for preventing or treating a disease and use of a pyridazinone derivative compound - Google Patents

Abstract

PYRIDAZINONE DERIVED COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR PREVENTING OR TREATING A DISEASE AND USE OF A PYRIDAZINONE DERIVED COMPOUND Compound derived from pyridazinone shown by the following formula (1): in which R ^ 1 ^ is selected from hydrogen, etc. ; R ^ 2 ^ is selected from substituted aryl, etc .; R ^ 3 ^ is hydrogen, etc .; p is O, 1 or 2; each R ^ 4 ^ and R ^ 5 ^ are hydrogen, etc .; R ^ 6 ^ and R ^ 7 ^ join to form a group of the formula: in which R ^ 8 ^ is hydrogen, X is selected from oxygen, etc .; R ^ 10 ^ is selected from hydrogen, etc .; R ^ 11 ^ is selected from hydrogen, etc .; R ^ 12 ^ is selected from hydrogen, etc .; R ^ 13 ^ is selected from hydrogen, etc .; R ^ 14 ^ R is selected from hydrogen, etc .; each m and n is O, 1, or 2, or a pharmaceutically acceptable salt thereof, which is useful as a medicine.

Description

"PYRIDAZINONE DERIVATIVE COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD FOR PREVENTION OR TREATMENT OF A DISEASE AND USE OF A PYRIDAZINONE DERIVATIVE COMPOUND"

Field of the invention

The present invention relates to a pyridazinone derivative compound and a salt thereof, which are useful for medicaments. Technique History

Rheumatoid arthritis is a systemic inflammatory disease mainly caused by arthrosynovium. In general, methotrexate (MTX) is now used as a disease-modified antirheumatic drug (DMARD), but efficacy for inflammatory responses or "arthritis mutilans" (a severe deforming polyarthritis with gross destruction of bones and cartilage, usually a atypical form of rheumatoid arthritis) is not sufficient. On the other hand, biologics, which are targeted cytokines (TNF, IL-I, IL-6), have recently revealed their efficacy for RAi and the importance of these cytokines in RA manifestation has been proven. In particular, monoclonal TNF antibody REMICADE and soluble TNF receptor fusion protein ENBREL, which inhibits TNF function, are noteworthy because of unprecedented efficacy not only for inflammatory response but for "arthritis mutilans".

However, the above fact suggests that in the future the importance of treatment for RA, these biologics have fundamental disadvantages related to cost per patient, production efficiency, administration limitation for hypodermic or intravenous injection, and so on. Thus, in the next generation anti-RA drugs are expected to overcome these problems, that is, drugs that are orally small molecules that selectively block or modulate the function of these cytokines. In particular mitogen-activated protein kinase ρ3 8α (MAPK p3 8a) is part of intracellular phosphorylation kinase participating in cytokine production and / or functional expression (TNF, IL-I, IL-6), and MAPK p38a is reported. It is activated in the arthrosynovia of RA patients thus producing excessively cytokines so that MAPK p38a is attracted as an anti-RA drug target.

These compounds or anti-inflammatory agents having cytokine inhibitory activity have been described (WO 98/22457, WO 00/41698, WO 00/43384, WO 01/22965, WO 02/07772, WO 02/58695, WO 03/041644, etc. ), but as far as we know, a new pyridazinone derivative having this activity is new.

Summary of the invention

The present invention relates to a pyridazinone derivative compound and a pharmaceutically acceptable salt thereof, which are useful as medicaments; a pharmaceutical composition comprising as an active ingredient said pyridazinone derivative compound or a pharmaceutically acceptable salt thereof; a use of said pyridazinone derivative compound or a pharmaceutically acceptable salt thereof for therapeutic purposes, comprising administering to a mammal said pyridazinone derivative compound or a pharmaceutically acceptable salt thereof.

The pyridazinone derivative compound and a pharmaceutically acceptable salt thereof are inhibitors of cytokine production or transduction thereof, and by inhibiting MAPK p38a they possess pharmacological actions such as analgesic action, antiinflammatory action, anti arthritis mutilans action, or similar.

They are useful as an analgesic, in particular anti-RA agent, pain drug and other conditions associated with inflammation, Crohn's disease drug, inflammatory bowel disease drug, psoriasis drug, or the like.

The pyridazinone derivative compound or a salt thereof of the present invention is a pyridazinone derivative compound shown by the following formula (I) (hereinafter simply referred to as compound (I)): <formula> formula see original document page 4 </ formula >

wherein R is hydrogen, group consisting of substituted or unsubstituted, is selected from substituted lower alkyl and substituted or unsubstituted aryl; R "2 is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; R3 is lower alkyl; ρ is 0, 1 or 2: and each R4 and R5 are hydrogen or joined to form a bond; R6 and R7 are joined to form a group of the formula:

wherein R8 is hydrogen, X is oxygen or N-R9, wherein R9 is hydrogen, substituted or unsubstituted lower alkylanyl or substituted or unsubstituted lower alkyl and substituted or unsubstituted aryl; or R8 and R9 may be joined to form a bond; every m and η

are 0, 1 or 2; each R10 and R12 are selected from the group consisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino; substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted lower alkoxycarbonyl and substituted or unsubstituted acyloxy; each R 11, R 13 and R 14 are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, carboxy and substituted or unsubstituted lower alkoxycarbonyl; R10 and R11 or R12 and R14 may be joined to form substituted or unsubstituted oxo, hydroxyimino, lower alkylene in which one or more carbon atoms may be substituted by heteroatoms, or substituted or unsubstituted lower alkylidene; R 9 and R 10 may join to form lower alkylidene or a bond; R11 and R13 or R13 and R14 may join to form a bond; provided that when η = 1 and R10, R11, R12, R13 and R14 are simultaneously hydrogen, R9 will be substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkanoyl or a pharmaceutically acceptable salt thereof.

One of the preferred embodiments of the present invention may be represented by compound (I) wherein R1 is hydrogen or substituted or unsubstituted aryl, R2 is substituted or unsubstituted aryl; ρ is 0; each R4 and R5 are hydrogen or joined to form a bond; and R6 and R7 join to form a group of the formula:

<formula> formula see original document page 5 </formula>

wherein R8 is hydrogen; X is oxygen or N-R 9, wherein R 9 is hydrogen, substituted or unsubstituted lower alkanoyl or substituted or unsubstituted lower alkyl; or R8 and R9 may be joined to form a bond; each m and η are 0, 1 or 2; each R10 and R12 are selected from the group consisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino; substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted lower alkoxycarbonyl and substituted or unsubstituted acyloxy; each R 11, R 13 and R 14 is selected from the group consisting of substituted or unsubstituted hydrogen, halogen and lower alkyl; R10 and R11 or R12 and R14 may be joined to form substituted or unsubstituted oxo, hydroxyimino, lower alkylene in which one or more carbon atoms may be substituted by heteroatoms, or substituted or unsubstituted lower alkylidene; R 9 and R 10 may join to form lower alkylidene or a bond; R11 and R13 or R13 and R14 may join together to form a bond, provided that when η = 1 and R10, R11, R12, R13 and R14 are simultaneously hydrogen, R9 will be substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkanoyl. or a pharmaceutically acceptable salt thereof.

Another preferred embodiment of the present invention may be represented by compound (I), wherein R1 is hydrogen or C6-14 aryl optionally substituted by C1-6 alkyl or C1-6 alkylamino sulfonyl; R2 is C6-14 aryl optionally substituted by 1 to 3 substituents selected from halogen, C1-6 alkyl and C1-6 alkoxy; foot 0; each R4 and R5 are hydrogen or joined to form a bond; and R6 and R7 join to form a group of the formula:

R8 wherein R8 is hydrogen; X is oxygen or N-R 9i wherein R 9 is hydrogen, C 1-6 alkyl, optionally substituted by carboxy, hydroxy, C 1-6 alkoxycarbonyl, morpholino, morpholino carbonyl or C 1-6 alkylsulfonyloxy. or C 2-7 alkanoyl; or R8 and R9 may join to form a bond; each m and η are 0, 1 or 2; R10 is hydrogen or C1-6 alkyl optionally substituted by (C6-14 aryl) C1-6 alkoxy / di (C6 -C14 aryl) alkylsilyloxy or hydroxy; R11 is hydrogen or C1-6 alkyl; R12 is selected from the group consisting of hydrogen; halogen; hydroxy; carboxy; formyl; cyan; C1-6 alkyl optionally substituted by hydroxy, hydroxyimino, halogen, C1-6 alkoxy, C1-7 alkanoyloxy, amino, mono or di (C1-6 alkylamino) (wherein one or both of said C1-6 alkyl. 6 are optionally substituted by hydroxy, C 1-6 alkoxy, C 6 -C 14 aryl or (C 36 cycloalkyl) carbonyl, C 1-6 alkylureido, morpholino, or 4-6 membered cyclic amino optionally substituted by hydroxy, C 1-6 alkyl 6 or di (C 1-6 alkylamino); mono or di (C 1-6 alkylamino); 4-6 membered cyclic amino; C 1-6 alkoxy optionally substituted by 15 C 6 -C 14 aryl; carbamoyl optionally substituted by C 3 cycloalkyl -6 or hydroxy (C1-6 alkyl); (C1-6 alkoxy) carbonyl; and (C1-4 alkoxycarbonyloxy; R13 is hydrogen, or C1-6 alkyl optionally substituted by hydroxy or C1-7 alkanoyloxy ; R 14 is hydrogen; R 10 and 20 R 11 may be joined to form C 2-6 alkylene in which one or more carbon atoms may be substituted and (heteroatoms, which are optionally substituted by (C6 -C14 aryl) C1-6 alkoxycarbonyl or C1-7 alkanoyl); R 12 and R 13 may be joined to form C 2-6 alkylene in which one or more carbon atoms may be substituted with heteroatoms, which are optionally substituted by C 1-6 alkyl optionally substituted by hydroxy, or C 1-7 alkanoyl optionally substituted by C1-6 alkoxy; C 1-6 alkylidene optionally substituted by hydroxy; oxo; or hydroxyimino; R 9 and R 10 may join to form C 1-6 alkylidene or a bond; R11 and R13 may join to form a bond; R 13 and R 14 may be joined to form a bond, provided that when R = 1 and R 10, R 11, 35 R 12, R 13 and R 14 are simultaneously hydrogen, R 9 will be substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkanoyl; or a pharmaceutically acceptable salt thereof. Detailed Description of the Invention

Compound (I) and a salt thereof of the present invention may be prepared by the following processes.

Process 1

<formula> formula see original document page 8 </formula>

Process 2

<formula> formula see original document page 8 </formula> Process 3

<formula> formula see original document page 9 </formula>

Process 4

<formula> formula see original document page 9 </formula>

Process 5

<formula> formula see original document page 9 </formula> Process 6

<formula> formula see original document page 10 </formula>

Process 7

<formula> formula see original document page 10 </formula>

Process 8

<formula> formula see original document page 10 </formula> In the above-mentioned process formulas R1, R2, R3, R4, R5, R6i R7, R8, R9, R107 R11i R12, R13, R13, m, η and ρ are as defined above: R 12 'is similar to R 12; R12a is C1-6 alkyl (e.g. methyl, ethyl, propyl, n-butyl, tertiary butyl, pentyl, hexyl, etc.); and Hal is a halogen atom (e.g. chlorine, bromine, iodine). For example, Process 1 is exemplified by Example 1 or the like; Process 2 is exemplified by Example 6 or the like; Process 3 is exemplified by Example 15 or the like; Process 4 is exemplified by Example 2 or the like; Process 5 is exemplified by Example 6 and Example 60, successively, or the like; Process 6 is exemplified by Example 55 or the like; Process 7 is exemplified by Example 125 or the like; and Process 8 is exemplified by Example 131 or the like.

In addition to the processes mentioned above, compound (I) and a salt thereof may be prepared, for example, according to the procedures illustrated in the Examples of this report or in similar ways.

The starting compounds may be prepared, for example, according to the procedures illustrated in the Preparations of this report or in similar ways.

Compound (I) and a salt thereof may be prepared according to the methods shown in Preparations or Examples, or in ways similar thereto. Note that all solvated forms of compound (I) (eg hydrates, ethanolates, etc.), all stereoisomers of compound (I) (eg enantiomers, diastereoisomers, racemic compounds, etc.) and crystalline forms of compound (I) also fall within the scope of the present invention.

Note that derivatives of radioisotope-labeled compound (I), which are suitable for biological studies, also fall within the scope of the present invention.

Suitable salts of the subject compound (I) are those conventionally pharmaceutically acceptable and include metal salts such as alkali metal salts (e.g. sodium salts, potassium salts, etc.) and alkaline earth salts (e.g. salts calcium, magnesium salts, etc.), ammonium salts, organic base salts (for example trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, di (cyclohexylamine) salts, N, N'-di-benzylethylenediamine, etc.), salts of organic acids (eg acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), organic acid salts ( eg chloride, bromide, iodide, sulfate, phosphate, etc.), a salt with an amino acid (eg arginine, aspartic acid, glutamic acid, etc.), etc. All starting materials and product compounds may be salts. The compounds of the above processes may be converted to salts according to a conventional method. The following explains in detail the symbols of formula (I). From beginning to end of the report and claims, the term "lower" is intended to mean from 1 to 6 carbon atoms unless otherwise indicated.

Definition of R1

In formula (I), R 1 is selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted aryl. Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R1 may include straight or branched C1S alkyls such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terciobutyl, pentyl, hexyl, etc., in which a preferred one may be C1-4 alkyl, and more preferably one may be methyl, ethyl, propyl, isopropyl, isobutyl, etc.

Examples of the substituents for the "substituted lower alkyl" for R 1 may be hydroxy, hydroxy (C 5-8 cycloalkyl), C 5-8 cycloalkyl nitro, nitro (C 5-8 cycloalkyl), starch (C 5-8 cycloalkyl) starch , sulfonamido, sulfonamido (C 5-8 cycloalkyl), ureido, ureido (C 5-8 cycloalkyl), etc. The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different.

Examples of the "aryl" of the "substituted or unsubstituted aryl" for R1 may include C6-n aryl such as phenyl, naphthyl, indenyl, anthryl, etc., in which a preferred may be C6-10 aryl, and the most preferred. Preferred may be phenyl, etc.

Examples of "substituted lower aryl" substituents for R1 may include lower alkyl (e.g. C1-4 alkyl alkyl (e.g. methyl, ethyl, propyl, butyl, etc.), etc.), (C1-4 alkyl). -4) aminosulfonyl (eg methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, tertiary butyl aminosulfonyl, etc.), aryloxy (eg C6.14 aryloxy, etc.), halo (lower alkyl) (eg chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachloroethyl, etc.), hydroxy (lower alkyl) (e.g. hydroxy (C1-4 alkyl, etc.), lower alkanoyl (e.g. (C1-4 alkyl) carbonyl, etc.), halogen (eg fluorine, chlorine, bromine, iodine, etc.), carboxy, lower alkoxycarbamoyl, carbamoyl, (lower alkyl) carbamoyl, etc. The number of substituents may be one or two or more. two or more substituents may be the same or different Suitable examples of R 1 may include hydrogen, methyl phenyl, (tertiary butylamino) sulfonyl phenyl, ethyl phenyl, methoxy phenyl, aminosulfonyl phenyl, etc.

R2 definition

In formula (I), R 2 is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

Examples of the "aryl" of the "substituted or unsubstituted aryl" for R2 may include aryls similar to those above exemplified for R1, in which one preferred may be C6-10 aryl, and most preferred may be phenyl, etc.

Examples of the "substituted lower aryl" substituents for R2 may include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), lower alkyl (e.g. C1-4 alkyl alkyl (e.g. methyl, ethyl , propyl, butyl, etc.), etc.), lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, butoxy, etc.)), etc. halo (lower alkyl) (e.g. chloromethyl, dichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentachlorethyl, etc.), hydroxy (lower alkyl), etc. Where the number of substituents is two or more, the substituents may be the same or different. substituted or unsubstituted heteroaryl "for R2 may include 5-14 membered heteroaryl groups such as furyl, pyrrolyl, thienyl, and the like.

Examples of substituents for "substituted heteroaryl" for R2 may include substituents similar to the substituents above exemplified for "substituted aryl" for R2. The number of substituents may be one or two or more. Where the number of substituents is two or more, the substituents may be the same or different.

Suitable examples of R2 may include phenyl, fluorophenyl, difluorophenyl, chlorofluorophenyl, methylphenyl, dimethylphenyl, methoxyphenyl, methyl (fluoro) phenyl, etc.

Definition of R3

In formula (I), R3 is lower alkyl.

Examples of the "lower alkyl" for R3 may include lower alkyls similar to those above exemplified for R1, in which the preferred may be C1-4 alkyl.

Suitable examples of R3 may be methyl, ethyl, etc. Definition of ρ

In formula (I), ρ is 0, 1 or 2. Suitable example of ρ is 0.

R4 and R5 Definitions

In formula (I) each R 4 and R 5 are hydrogen or joined to form a bond.

R6 and R7 definitions

In formula (I), R6 and R7 join to form a group of the formula:

<formula> formula see original document page 15 </formula>

Definition of R8

R8 is hydrogen. X definition

X is oxygen or N-R 9, wherein R 9 is hydrogen, substituted or unsubstituted lower alkanoyl, or substituted or unsubstituted lower alkyl. Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R 9 may include lower alkyls similar to those exemplified above for R 1.

Examples of substituents for the "substituted or unsubstituted lower alkyl" for R9 may include those exemplified as the substituents for the "substituted lower alkyl" for R18 and R19 mentioned below, wherein the preferred are carboxy, hydroxy, (C1-4 alkoxy). 6) carbonyl, morpholino, morpholino carbonyl or (C1-6 alkyl) sulfonyloxy.

Examples of "lower alkanoyl" of "substituted or unsubstituted lower alkanoyl" for R 9 may include C 2-7 alkanoyl (e.g. (C 1-6 alkyl) carbonyl (e.g. acetyl, ethylcarbonyl, propylcarbonyl, butyl -carbonyl, pentylcarbonyl, hexylcarbonyl, etc.), etc.).

Examples of substituents for "substituted lower alkanoyl" for R9 may include those exemplified as substituents for the "substituted lower alkyl" for R18 and R19 mentioned below. Preferred examples of R 9 may include hydrogen; C 1-6 alkyl optionally substituted by carboxy, hydroxy, (C 1-6 alkoxy) carbonyl, morpholino, morpholino carbonyl or (C 1-6 alkyl) sulfonyloxy; C2-7 alkanoyl, etc.

Alternatively, R8 and R9 may join to form a bond.

Definitions of m and η Each m and η is 0, 1, or 2. Definitions of R10 and R11

In formula (I), R 10 is selected from the group consisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted carbamoyl or unsubstituted, carboxy and substituted or unsubstituted lower alkoxycarbonyl. Specifically, R10 is substituted or unsubstituted lower alkyl or hydrogen.

Examples of "lower alkyl" for "substituted or unsubstituted lower alkyl" for R10 may include lower alkyls similar to those exemplified above for R1, where preferred may be C1-6 alkyl and more preferred may be methyl, ethyl, isopropyl. , etc.

Examples of the "substituted lower alkyl" substituents for R10 may include: (1) hydroxy; (2) aryl alkoxy (e.g., (C6-14 aryl) C1-6 alkoxy, etc.); (3) di (C6-14 aryl) C1-6 alkyl siloxy (e.g. methyl diphenyl silyloxy, tertiary butyl diphenyl silyloxy, etc.) / etc.

Examples of "substituted or unsubstituted amino", "substituted or unsubstituted lower alkoxy", "saturated cyclic amino", "substituted or unsubstituted carbamoyl" and "lower alkoxycarbonyl" for R10 may be similar to those of "amino substituted or unsubstituted "," substituted or unsubstituted lower alkoxy "," saturated cyclic amino "," substituted or unsubstituted carbamoyl "and" lower alkoxycarbonyl "exemplified above as the substituents for" substituted lower alkyl "for R12 mentioned below.

Alternatively, R 9 and R 10 may be joined to form lower alkylene (e.g., C 2-6 alkylene and such as ethylene, propylene, butylene, pentylene, hexylene, etc.) in which propylene, etc. may be preferred. R11 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, carboxy, and substituted or unsubstituted lower alkoxycarbonyl.

Examples of halogen for R11 may include chlorine, fluorine, bromine, iodine, etc.

Examples of "lower alkyl" for "substituted or unsubstituted lower alkyl" for R11 may include lower alkyls similar to those exemplified above for R1, and examples of "lower alkoxycarbonyl" for "substituted or unsubstituted lower alkoxy" for R11 may include those exemplified above as the substituent (8) for the "lower alkyl substituted" for R 12 mentioned below. Examples of the substituents for "substituted lower alkyl" and "substituted lower alkoxycarbonyl" for R11 may include those exemplified as substituents for "substituted lower alkyl" for R1.

Specifically, R11 is hydrogen, or lower alkyl. Lower alkyl examples for R11 may include lower alkyls similar to those exemplified above for R1, where preferred may be C1-4 alkyl and more preferred may be methyl, ethyl, propyl, etc. .

Alternatively, R10 and R11 may be joined to form (1) substituted or unsubstituted lower alkylene (e.g., C2.6 alkylene (e.g., ethylene, propylene, butylene, pentylene, hexylene, etc.), where preferred may be ethylene, propylene, butylene, etc.); (2) substituted or unsubstituted lower alkylidene (e.g. C1-6 alkylidene such as methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, etc., wherein a preferred may be methylidene, ethylidene, propan-2-ylidene , etc.); (3) oxo, or (4) hydroxyimino, etc.

As used herein, the term "lower alkylene" in the phrase "substituted lower alkylene" formed by R 10 and R 11 may also include alkylene group as defined above wherein one or more carbon atoms are substituted by one or more heteroatoms selected from atoms nitrogen, oxygen and sulfur, and examples of such substituted lower alkylenes formed by R10 and R11 may include following groups such as, but not limited to - (CH2) 2-O- (CH2) 2-, - (CH2) 2- N- (CH2) 2-, etc.

Examples of the substituents for the above-mentioned "substituted lower alkylene" formed by R10 and R11 together may include: (1) aryl alkoxycarbonyl (e.g. (C6-14 aryl) C1-6 alkoxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl, etc. .); (2) acyl (e.g., C1-7 alkanoyl such as formyl, acetyl, propionyl, butyryl, etc.), C6-14 acyl such as benzoyl, etc.

Preferred examples of the "substituted or unsubstituted lower alkylene" formed by R 10 and R 11 may include C 2-6 alkylenes in which one or more carbon atoms may be substituted by heteroatoms selected from oxygen and nitrogen atoms, which is optionally substituted by ( C6-14 aryl) C1-7 alkoxycarbonyl or C1-7 alkanoyl.

Alternatively, R 9 and R 10 may be joined to form lower alkylene or a bond.

Examples of the "lower alkylene" formed by R 9 and R 10 may include C 2-6 alkylene, in which propylene, etc. is preferred. Definitions of R12, R13 and R14 In the above formula (I), R12 is selected from the group consisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino, substituted or unsubstituted lower alkoxy substituted, saturated cyclic amino, substituted or unsubstituted carbamoyl, carboxy and substituted or unsubstituted lower alkoxycarbonyl, substituted or unsubstituted acyloxy. Examples of the "halogen" for R 12 may include chlorine, fluorine, bromine, iodine, etc., where fluorine, etc. may be preferred.

Examples of "lower alkyl" for "substituted or unsubstituted lower alkyl" for R 12 may include lower alkyls similar to those exemplified above for R 1, where preferred may be C 1-4 alkyl and more preferred may be methyl, ethyl, isopropyl, etc. .

Examples of the "substituted lower alkyl" substituents for R12 may include: (1) hydroxy, hydroxyimino or tri (lower alkyl) silyloxy; (2) halogen (eg chlorine, fluorine, bromine, iodine, etc.); (3) substituted or unsubstituted amino (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) amino), wherein said C1-6 alkyl may be substituted by C14-4 aryl (C3-8 cycloalkyl) carbonyl or hydroxy (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, terciobutylamino, neopentylamino, hydroxymethylamino, hydroxyethylamino, cyclopropane carbonylamino, etc.), di (alkyl) C1-4) amino, in which one or both of said C1-4 alkyl may be substituted with C6-4 aryl (e.g., dimethylamino, diethylamino, ethyl methylamino, etc.), 2-hydroxyethylamino, 2-methoxyethylamino, 2- (dimethylamino) ethylamino, 2-hydroxy-1,1-dimethylethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl) methylamino, benzylmethylamino, tertiary butyl benzylamino, dibenzylamino, etc.), mono (C 2-7 alkanoyl) amino (e.g. acetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, b ut arylcarbonylamino, pentylcarbonylamino, hexylcarbonylamino, etc.), (C 3-8 cycloalkyl) amino (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (4) substituted or unsubstituted lower alkoxy (e.g. C 1-6 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, neopentyloxy, etc.), (C 6 -C 14 aryl) C 1-6 alkoxy (e.g. benzyloxy, etc.), 2-hydroxy ethyloxy, 2-hydroxy-1,1-dimethyl ethyloxy, 2-methoxyethyloxy, 2- (dimethylamino) ethyloxy, etc.); (5) saturated cyclic amino (e.g., 4-, 5- or 6-membered saturated cyclic amino which may further have heteroatoms selected from nitrogen, oxygen and sulfur atoms and / or oxo in addition to amino nitrogen and may have substituents such as azetidinyl (e.g. 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl, 3-methylamino-1-azetidinyl, etc.), pyrrolidinyl (e.g. 1-pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl, 3-amino-1-pyrrolidinyl, 3-methylamino-1-pyrrolidinyl, etc.), morpholinyl (e.g. morpholine, etc.), 4-lower alkyl-1-piperazinyl (e.g. 4-methyl-1-piperazinyl , 4-isopropyl-1-piperazinyl, etc.), 4- [mono or di (lower alkyl) amino] (e.g. 4- (dimethylamino) -1-piperidinyl, etc.), oxopyrrolidinyl (e.g. 2-oxo -1-pyrrolidinyl, etc.), etc.); (6) substituted or unsubstituted carbamoyl (e.g. carbamoyl, (lower alkyl) carbamoyl (e.g. (C1-4 alkyl) carbamoyl such as methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, isopropyl carbamoyl, isopropyl carbamoyl, butyl carbamoyl, etc.), (C 3-8 cycloalkyl) carbamoyl (e.g., cyclopropyl carbamoyl, etc.), etc.); (7) carboxy; (8) (lower alkoxy) carbonyl (e.g. (C1-6 alkoxy) carbonyl (e.g. methoxy carbonyl, ethoxy carbonyl, propyloxy carbonyl, tertiary butoxy carbonyl, pentyloxy carbonyl, hexyloxy carbonyl, etc.), etc.); (9) (lower alkyl) ureido (e.g., (C1-6 alkyl) ureido (e.g. methyl ureido, ethyl ureido, etc.)); (10) lower acyloxy (e.g. C1-7 alkanoyloxy (e.g. formyloxy, acetyloxy, ethyl carbonyloxy, propyl carbonyloxy, butyl carbonyloxy, pentyl carbonyloxy, hexyl carbonyloxy, etc.), etc.).

The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different.

Examples of "substituted or unsubstituted amino", "saturated cyclic amino", "substituted or unsubstituted lower alkoxy", "substituted or unsubstituted carbamoyl" and "(lower alkoxy) carbonyl" for R12 may be similar to those of "substituted amino" or unsubstituted "," saturated cyclic amino "," substituted or unsubstituted lower alkoxy "," substituted or unsubstituted carbamoyl "and" (lower alkoxy) carbonyl "exemplified above as substituents of the" substituted lower alkyl "for R12.

Examples of "acyloxy" for "substituted or unsubstituted acyloxy" for R12 may include the lower acyloxy exemplified above as the substituent (10) for the above-mentioned "substituted lower alkyl" for R12. Examples of the substituents for the "substituted acyloxy" for R 12 may be similar to those exemplified as the substituents for the "substituted lower alkyl" for R 12.

Preferred examples for R 12 include hydrogen; halogen; hydroxy; carboxy; formyl; cyan; hydroxy cyano, C1-6 alkyl optionally substituted by hydroxy, hydroxyimino, halogen, C1-6 alkoxy, C1-7 alkanoyloxy, amino, mono or di (C1-amino alkyl) wherein one or both C1-6 alkyl Are optionally substituted by hydroxy, C 1-6 alkoxy, C 6-14 aryl or (C 3-6 cycloalkyl carbonyl), (C 1-6 alkyl) ureido, morpholino, C 1-7 alkanoyloxy or cyclic amino optionally substituted hydroxy, C 1-6 alkyl or di (C 1-6 alkyl) amino, C 1-6 alkoxy optionally substituted by C 3-6 cycloalkyl or hydroxy (C 1-6 alkyl) optionally substituted carbamoyl C 3-6 cycloalkyl or hydroxy (C 1-6 alkyl), (C 1-6 alkoxy) carbonyl, (C 1-6 alkoxy) carbonyloxy, etc.

Among the substituents mentioned above, suitable examples of R 12 may include hydrogen, fluorine, hydroxy, formyl, cyano, methyl, amino methyl, tertiary butylamino methyl, dimethylamino methyl, diethylamino methyl, dibenzylamino methyl, benzyl methyl terciobutylamino, methoxy carbonyl methyl , 3-hydroxy azetinyl methyl, 4-methylpiperazinyl methyl, pyrrolidinyl methyl, hydroxymethyl, hydroxy ethylamino methyl, methoxy ethylamino methyl, iodine methyl, methylamino methyl, (2-hydroxymethyl) methylamino methyl, acetyloxy methyl, 4- (dimethylamino) -1-piperidinyl methyl, ethoxy carbonyl methyl, cyclopropyl carbamoyl methyl, ethyl ureido methyl, hydroxyimino methyl, dimethylamino, isopropylamino, 3-hydroxy-1-azetidinyl, piperidino, morpholine, benzyloxy, neopentyloxy, carboxy, carboxy carbonyl, tertiary butoxy carbonyl, carbamoyl, cyclopropyl carbamoyl, etc. R13 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, carboxy and (unsubstituted substituted lower alkoxy) carbonyl.

Examples of the "halogen" and "(substituted or unsubstituted lower alkoxy) carbonyl" for R 13 may be similar to those exemplified for R 11.

Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R 13 may include lower alkyls similar to those exemplified above for R 1, preferred may be a C 1-4 alkyl, and more preferred may be methyl, ethyl, isopropyl, etc.

Examples of the "substituted lower alkyl" substituents for R13 may include (1) hydroxy; (2) halogen (eg chlorine, fluorine, bromine, iodine, etc.); (3) substituted or unsubstituted amino (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, terciobutylamino, neopentylamino, etc.), di (C1-4 alkyl) amino (e.g. dimethylamino, diethylamino, ethyl methylamino, etc.), 2-hydroxyethylamino, 2-methoxy ethylamino, 2- (dimethylamino) ethylamino , 2-hydroxy-1,1-dimethyl ethylamino, 2-hydroxy-1- (hydroxymethyl) ethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl) methylamino, etc.), mono (C 2-7) amino alkanoyl (e.g. acetylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, pentylcarbonylamino, hexylcarbonylamino, etc.), (C 3-8 cycloalkyl) amino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (4) substituted and unsubstituted lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 2-hydroxyethyloxy, 2-hydroxy-1,1-dimethyl ethyloxy, 2-methoxy ethyloxy, 2- (dimethylamino) ethyloxy, etc.); (5) lower alkanoyloxy (e.g. C1-7 alkanoyloxy (e.g. formyloxy, acetyloxy, ethyl carbonyloxy, propyl carbonyloxy, butylcarbonyloxy, pentyl carbonyloxy, hexyl carbonyloxy, etc.), etc.).

The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different.

Suitable examples of R13 may include hydrogen, halogen (e.g. fluorine, etc.), C1-6 alkyl optionally substituted by hydroxy, fluorine, halogen, C1-6 alkoxy or C1-7 alkanoyl (e.g. methyl, hydroxymethyl, fluoromethyl, methoxy methyl, acetyloxymethyl, etc.), of which hydrogen, halogen, C1-6 alkyl optionally substituted by hydroxy or C1-7 alkanoyloxy (e.g. hydroxymethyl, acetyloxymethyl, etc.) are preferred, etc. . R14 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, carboxy, and substituted or unsubstituted lower alkoxycarbonyl.

The "halogen", "substituted or unsubstituted lower alkyl" or "substituted or unsubstituted lower alkoxycarbonyl" for R14 may be similar to those exemplified for R11. Preferably R14 is hydrogen.

Alternatively, R 12 and R 13 may be joined to form (1) substituted or unsubstituted lower alkylene (e.g., C 2-6 alkylene (e.g., ethylene, propylene, butylene, pentylene, hexylene, etc.), wherein a preferred may be be ethylene, propylene, butylene, etc.)); (2) substituted or unsubstituted lower alkylidene (e.g. C1-6 alkylidene such as methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, etc., wherein a preferred may be methylidene, ethylidene, propan-2-ylidene, etc. .); (3) oxo, or (4) hydroxyimino. The term "lower alkylene" in the phrase "substituted or unsubstituted lower alkylene" for R 12 and R 13 refers to the above defined alkylene group in which one or more carbon atoms are substituted by one or more heteroatoms selected from nitrogen, oxygen and sulfur.

Examples of the substituents for the "substituted lower alkylene" formed by R 12 and R 13 may include (1) substituents for o. "substituted or unsubstituted lower alkyl" for R 12; and (2) substituted or unsubstituted lower alkyl (e.g. C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, pentyl, hexyl, etc.), examples of the substituent may include substituents for the "substituted or unsubstituted lower alkyl" for R12).

Suitable examples of the "substituted or unsubstituted lower alkylene" formed by R12 and R13 may include following groups such as, but not limited to, - (CH2) 4-, - (CH2) 5-, - (CH2) 2-O- (CH2) 2-, - (CH2) 2-S- (CH2) 2-, -CH2-N-CH2 -, -CH-N-CHr, -O- (CH2) 2-O-, - (CH2) 2-SO2- (CH2) 2-, 20- (CH2) 2-N- (CH2) 2-,

<formula> formula see original document page 25 </formula>

(CH2) 2-N- (CH2) 2- - (CH2) 2-N- (CH2) 2- - (CH2) 2-N- (CH2) 2 "

<formula> formula see original document page 25 </formula>

- (CH2) 2-N- (CH2) 2- - (CH2) 2-N- (CH2) 2-

<formula> formula see original document page 25 </formula>

etc.

Examples of the substituents for the above-mentioned "substituted lower alkylidene" formed by R12 and R13 may be similar to those exemplified for the "substituted or unsubstituted alkylene" formed by R12 and R13.

Suitable examples of the "substituted lower alkylidene" formed by R 12 and R 13 may include C 1-6 alkylidene optionally substituted by hydroxy, such as the following groups, but not limited to, = CH 2, = CH-CH 3, = CH-CH 2 -OH, etc. .

Alternatively, R11 and R13 or R13 and R14 may join to form a bond.

In an embodiment of the present invention, R 6 and R 7 join to form the following structure (A), (B1) or (B2).

<formula> formula see original document page 26 </formula>

Definition of R15

In the above-mentioned formula A, R15 is selected from the group consisting of hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino, substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted or unsubstituted lower carbamoyl, carboxy and substituted alkoxycarbonyl or not replaced.

Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R15 may include lower alkyls similar to those exemplified above for R1, wherein a preferred may be C1-4 alkyl and most preferred may be methyl, ethyl, isopropyl, etc. .

Examples of "substituted lower alkyl" substituents for R15 may include: (1) hydroxy; (2) substituted or unsubstituted amino (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) amino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino , tertiary butylamino, neopentylamino, etc. di (C1-6 alkyl) amino such as dimethylamino, diethylamino, ethyl methylamino, etc. 2-hydroxyethylamino, 2-methoxy ethylamino, 2- (dimethylamino) ethylamino, 2-hydroxy -1,1-dimethyl ethylamino, 2-hydroxy-1- (hydroxymethyl) ethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl) methylamino, etc.), mono (C 2-5 alkanoyl) amino (e.g. acetylamino, ethyl carbonylamino, propyl carbonylamino, isopropyl carbonylamino, butyl carbonylamino, etc.), (C 3-6 cycloalkyl) amino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (3) substituted or unsubstituted lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 2-hydroxyethyloxy, 2-hydroxy-1,1-dimethyl ethyloxy, 2- (dimethylamino) ethyloxy, etc.); (4) saturated cyclic amino (e.g., 4-, 5- or 6-membered saturated cyclic amino which may further have heteroatoms selected from nitrogen, oxygen and sulfur atoms and / or oxo in addition to amino nitrogen and may have substituents such as such as azetidinyl (eg 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl), pyrrolidinyl (eg 1-pyrrolidinyl etc.), morpholinyl (eg morpholine etc.), 4- lower alkyl-1-piperazinyl (e.g. 4-methyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, etc.), oxopyrrolidinyl (e.g. 2-oxo-1-pyrrolidinyl, etc.), etc.) ; (5) substituted or unsubstituted carbamoyl (e.g. carbamoyl, (lower alkyl) carbamoyl (e.g. (C1-4 alkyl) carbamoyl such as methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, isopropyl carbamoyl, butyl carbamoyl, etc.). ), etc.); (6) carboxy; (7) (lower alkoxy) carbonyl (e.g. (C1-S alkoxy) carbonyl (e.g., methoxy carbonyl, ethoxy carbonyl, tertiary butoxy carbonyl, pentyloxy carbonyl, hexyloxy carbonyl, etc.), etc.). The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different. Examples of "substituted or unsubstituted amino", "saturated cyclic amino", "substituted or unsubstituted lower alkoxy", "substituted or unsubstituted carbamoyl" substituted "and" (lower alkoxy) carbonyl "for R15 may be similar to those of" substituted or unsubstituted amino "," saturated cyclic amino "," substituted or unsubstituted lower alkoxy "," substituted or unsubstituted carbamoyl "and" ( lower alkoxy) carbonyl "exemplified above as substituents of the" substituted lower alkyl "for R15.

Suitable examples of R15 may include dimethylamino methyl, methylamino methyl, hydroxymethyl, morpholino, 3-hydroxy-1-azetidinyl, etc. Definitions of R16 and R17 In the above-mentioned formula (B1), R16 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted carbamoyl or unsubstituted, carboxy and (lower alkoxy) carbonyl.

Examples of the "halogen" for R16 may include chlorine, fluorine, bromine, iodine, etc., in which a preferred may be fluorine, etc.

Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R16 may include lower alkyls similar to those exemplified above for R1, wherein a preferred may be C1-4 alkyl and most preferred may be methyl, ethyl, isopropyl, etc.

Examples of "substituted lower alkyl" substituents for R16 may include: (1) hydroxy or tri (lower alkyl) silyloxy; (2) halogen (eg chlorine, fluorine, bromine, iodine, etc.); (3) substituted or unsubstituted amino (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) amino acids such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, terciobutylamino,

neopentylamino, etc .; di (C1-6 alkyl) amino such as dimethylamino, diethylamino, ethyl methylamino, etc .; 2-5 hydroxyethylamino, 2-methoxy ethylamino, 2- (dimethylamino) ethylamino, 2-hydroxy-1,1-dimethyl ethylamino, 2-hydroxy-1- (hydroxymethyl) ethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl ) methylamino, etc.), mono (C2-5) amino alkanoyl (e.g. acetylamino, ethyl carbonylamino, propyl carbonylamino, isopropyl carbonylamino, butyl carbonylamino, etc.), (C3-6) amino cycloalkyl (e.g. , cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (4) substituted or unsubstituted lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 2-hydroxy ethyloxy, 2-hydroxy-1,1 dimethyl ethyloxy, 2- (dimethylamino) ethyloxy, etc.); (5) saturated cyclic amino (e.g., 4-, 5- or 6-membered saturated cyclic amino which may further have heteroatoms selected from denitrogen, oxygen and sulfur and / or oxo atoms in addition to amino nitrogen and may have substituents such as azetidinyl (e.g. 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl), pyrrolidinyl (e.g. 1-pyrrolidinyl, etc.), morpholinyl (e.g. morpholine, etc.), lower 4-alkyl -1-piperazinyl (e.g. 4-methyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, etc.), oxopyrrolidinyl (e.g. 2-oxo-1-pyrrolidinyl, etc.), etc.); (6) substituted or unsubstituted carbamoyl (e.g. carbamoyl, (lower alkyl) carbamoyl (e.g. (C1-4 alkyl) carbamoyl such as methyl carbamoyl, ethyl carbamoyl, propyl carbamoyl, isopropyl carbamoyl, butyl carbamoyl, etc.). ), etc.); (7) carboxy; (8) (lower alkoxy) carbonyl (e.g. (C 1-6 alkoxy) carbonyl (e.g. methoxy carbonyl, ethoxy carbonyl, tertiary butoxy carbonyl, pentyloxy carbonyl, hexyloxycarbonyl, etc.), etc.). The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different.

Examples of "substituted or unsubstituted amino", "saturated cyclic amino", "substituted or unsubstituted lower alkoxy", "substituted or unsubstituted carbamoyl" and "(lower alkoxy) carbonyl" for R16 may be similar to those of "substituted amino" or unsubstituted "," saturated cyclic amino "," substituted or unsubstituted lower alkoxy "," substituted or unsubstituted carbamoyl "and" (lower alkoxy) carbonyl "exemplified above as substituents of the" substituted lower alkyl "for R7. Suitable examples of R16 may include hydrogen, fluorine, hydroxy, dimethylamino methyl, hydroxymethyl, methyl iodine, 4- (dimethylamino) -1-piperidinyl methyl, dimethylamino, piperidino, isopropylamino, methylamino methyl, morpholine, (2-hydroxyethyl) methylamino ethyl, 20 carboxy, methoxy carbonyl, tertiary butoxy carbonyl, 3-hydroxy-1-azetidinyl, etc.

In the above-mentioned formula (B1), R17 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, carboxy and 25 (lower alkoxy) carbonyl.

Examples of the "halogen" for R17 may include chlorine, fluorine, bromine, iodine, etc., in which a preferred may be fluorine, etc.

Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R 17 may include lower alkyls similar to those exemplified above for R 1, wherein a preferred may be C 1-4 alkyl and most preferred may be methyl, ethyl, isopropyl, etc. Examples of "substituted lower alkyl" substituents for R17 may include: (1) hydroxy; (2) halogen (e.g., chlorine, fluorine, bromine, iodine, etc.); (3) substituted or unsubstituted amino (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) amino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, terciobutylamino, neopentylamino, etc. di (C1-6 alkyl) amino such as dimethylamino, diethylamino, ethyl methylamino, etc .; 2-hydroxy ethylamino, 2-methoxy ethylamino, 2- (dimethylamino) ethylamino, 2-hydroxy-1,1-dimethyl ethylamino, 2-hydroxy-1- (hydroxymethyl) ethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl ) methylamino, etc.), mono (C2-5) amino alkanoyl (e.g. acetylamino, ethyl carbonylamino, propyl carbonylamino, isopropyl carbonylamino, butyl carbonylamino, etc.), (C3-6 cycloalkyl 15) amino (e.g. , cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (4) substituted or unsubstituted lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 2-20 hydroxy ethyloxy, 2-hydroxy-1,1 dimethyl ethyloxy, 2- (dimethylamino) ethyloxy, etc.). The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different.

Suitable examples of R17 may include hydrogen, methyl, fluorine, fluoromethyl, methoxy methyl, etc. Alternatively, R 16 and R 17 may be joined to form lower alkylene or lower alkylidene. Examples of the "lower alkylene" for R 16 and R 17 may include C 2-6 alkylene such as ethylene, propylene, butylene, pentylene, hexylene, etc., in which a preferred one may be ethylene, propylene, butylene, etc. Examples of the "lower alkylidene" may include C1-6 alkylidene such as methylidene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, etc., where a preferred one may be methylidene, ethylidene, propan-2-ylidene, etc. from R18

In the above-mentioned formula (B1), R18 is substituted or unsubstituted lower alkyl or hydrogen, provided that when both R1 and R17 are simultaneously hydrogen, R18 is substituted or unsubstituted lower alkyl.

Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R18 may include lower alkyls similar to those exemplified above for R1, wherein a preferred may be C1-4 alkyl and most preferred may be methyl, ethyl, propyl. , etc.

Examples of "substituted lower alkyl" substituents for R18 may include: (1) hydroxy; (2) carboxy; (3) halogen (chlorine, fluorine, bromine, iodine); (4) (lower alkoxy) carbonyl (e.g. (C1-6 alkoxy) carbonyl (e.g. methoxy carbonyl, ethoxy carbonyl, propyloxy carbonyl, butoxycarbonyl, terciobutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), etc. .); (5) substituted or unsubstituted amino (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) amino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino tert-butylamino, neopentylamino, etc. di (C1-6 alkyl) amino such as dimethylamino, diethylamino, ethyl methylamino, etc. 2-hydroxyethylamino, 2-methoxy ethylamino, 2- (dimethylamino) ethylamino, 2-hydroxy 1,1-dimethyl ethylamino, 2-hydroxy-1- (hydroxymethyl) ethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl) methylamino, etc.), mono (C 2 -s) amino alkanoyl (e.g. acetylamino , ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, butylcarbonylamino, etc.) (C3.6 cycloalkyl) amino (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (6) substituted or unsubstituted lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 2-hydroxy ethyloxy, 2-hydroxy-1,1-dimethyl ethyloxy , 2- (dimethylamino) ethyloxy, etc.); (7) saturated cyclic amino (e.g., 4-, 5- or 6-membered saturated cyclic amino which may further have heteroatoms selected from nitrogen, oxygen and sulfur atoms and / or oxo in addition to amino nitrogen and may have substituents such as such such as azetidinyl (eg 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl), pyrrolidinyl (eg 1-pyrrolidinyl, etc.), morpholinyl (eg morpholine, etc.), 4-alkyl lower-1-piperazinyl (e.g. 4-methyl-1-piperazinyl, 4-isopropyl-1-piperazinyl, etc.), oxopyrrolidinyl (e.g. 2-oxo-1-pyrrolidinyl, etc.), etc.); (8) (lower alkyl) sulfonyloxy (e.g. (C1-6 alkyl) sulfonyloxy (e.g. methyl sulfonyloxy, ethyl sulfonyloxy, propyl sulfonyloxy, butyl sulfonyloxy, pentyl sulfonyloxy, hexyl sulfonyloxy, etc.), etc.); (9) substituted or unsubstituted aryl sulfonyloxy (e.g., p-toluene sulfonyloxy, benzene sulfonyloxy, mesitylene sulfonyloxy, etc.), etc. The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different. Suitable examples of R18 may include hydrogen, methyl, ethyl, tertiary butoxycarbonylethyl, carboxyethyl, hydroxypropyl, methoxyethyl, hydroxyethyl, dimethylamino propyl, etc.

Definition of R19

In the above-mentioned formula (B2), R19 is hydrogen or substituted or unsubstituted lower alkyl. Examples of the "lower alkyl" of the "substituted or unsubstituted lower alkyl" for R19 may include lower alkyls similar to those exemplified above for R1, wherein a preferred may be C1-4 alkyl and most preferred may be ethyl, propyl, etc. Examples of "substituted lower alkyl" substituents for R19 may include: (1) hydroxy; (2) carboxy; (3) (lower alkoxy) carbonyl (e.g. (C1-6 alkoxy) carbonyl (e.g. methoxy carbonyl, ethoxy carbonyl, propoxycarbonyl, butoxycarbonyl, terciobutoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), etc. .); (4) saturated cyclic amino (e.g., 4-, 5- or 6-membered saturated cyclic amino which may further have heteroatoms selected from nitrogen, oxygen and sulfur atoms and / or oxo in addition to amino nitrogen and may have substituents such as such as azetidinyl (e.g., 3-hydroxy-1-azetidinyl, 3-amino-1-azetidinyl, etc.), morpholinyl (e.g., morpholino, etc.), etc.); (5) (saturated cyclic amino) carbonyl (e.g., a group in which the saturated cyclic amino exemplified above in (4) is attached to a carbonyl group (e.g. morpholine carbonyl, etc.), etc.) (6) (alkyl lower) sulfonyloxy (e.g. (C1-6 alkyl) sulfonyloxy (e.g. methyl sulfonyloxy, ethyl sulfonyloxy, propyl sulfonyloxy, butyl sulfonyloxy, pentyl sulfonyloxy, hexyl sulfonyloxy, etc.), etc.); (7) substituted amino or unsubstituted (e.g. amino, mono or di (substituted or unsubstituted lower alkyl) amino (e.g. mono (C1-6 alkyl) amino such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, terciobutylamino, neopentylamino, di. (Cies-alkyl) amino such as dimethylamino, diethylamino, ethyl methylamino, etc. 2-hydroxy ethylamino, 2-methoxy ethylamino, 2- (dimethylamino) ethylamino, 2-hydroxy-1,1-dimethyl ethylamino , 2-hydroxy-1- (hydroxymethyl) ethylamino, (2-hydroxyethyl) methylamino, (2-methoxyethyl) methylamino, etc.), m amino (C 2-6 alkanoyl) amino (e.g. acetylamino, ethyl carbonylamino, propyl carbonylamino, isopropyl carbonylamino, butyl carbonylamino, etc.), (C 3-6 cycloalkyl) amino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), etc.); (8) substituted or unsubstituted aryl sulfonyloxy (e.g. p-toluene sulfonyloxy, benzene sulfonyloxy, mesitylene sulfonyloxy, etc.), etc. substituted or unsubstituted lower alkoxy (e.g. C1-4 alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), 2-hydroxy ethyloxy, 2-hydroxy-1,1-dimethyl ethyloxy, 2- (dimethylamino) ethyloxy, etc.); (9) halogen (eg chlorine, fluorine, bromine, iodine, etc.), etc. The number of substituents may be one, two or more. Where the number of substituents is two or more, the substituents may be the same or different. Suitable examples of R19 may include hydrogen, methyl, ethyl, methoxy ethyl, methoxy propyl, hydroxy ethyl, ethoxy carbonyl ethyl, carboxyethyl, hydroxypropyl, morpholine carbonyl ethyl, methylamino propyl, dimethylamino propyl, etc.

Preferred examples of the preferred compound of the present invention may be exemplified by the Examples below. In order to show the usefulness of the compound (I) of the present invention, the results of pharmacological tests of representative compounds of the present invention are shown below.

Test 1: Inhibition of TNF-α Production in THP-I Cells [I] Test Method THP-1 cells, a human monocytic cell line, were maintained in RPMI 1640 (Sigma R8758) supplemented with penicillin (50 U / mL). , streptomycin (50 μg / mL) and 10% fetal bovine serum (Moregate BioTech.) at 37 ° C, 5% CO2 in a humidified incubator. Initial stock solutions of test compounds were prepared in DMSO. All cells, reagents and test compounds were diluted in culture media. THP-I (1 x 10 5 cells / final well) and lipopolysaccharide (LPS; 10 µg / ml final; Sigma L-4005, E. coli 055: B5 serotype) cells were added to 96-well culture plates. wells (Sumilon, MS-8196F5; sterile) containing test compound or 0.1% DMSO vehicle. The cell mixture was incubated for 20 hours in a humidified incubator at 37 ° C, 5% CO2. Culture supernatants were collected and TNF-α levels of LPS stimulated cells were calculated in the presence of 100 nM test compound compared to control cells stimulated in the presence of 0.1% DMSO.

[II] Test Compounds

(Example 1) - 6- {2- (2,4-difluoro phenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone.

(Example 2) - 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] pyrazol [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) - 3 (2H) -pyridazinone.

(Example 6) - 6 - [1-Ethyl - 6 - (4-fluorophenyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- (2-methyl phenyl ) -3 (2H) -pyridazinone.

(Example 35) - 6 - [2- (4-fluoro phenyl) -6,6-bis (hydroxymethyl)] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one.

(Example 37) 6- [2- (2,4-difluoro phenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - (2-methylphenyl) pyridazin-3 (2H) -one.

(Example 47) - 6- {2- (4-Fluoro-phenyl) -6 - [(4-methyl piperazin-1-yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a dihydrochloride] ] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one.

(Example 55) - 6- {2- (2,4-difluoro phenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 4,5-dihydropyridazin-3 (2H) -one.

(Example 57) - N-cyclopropyl-2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyrazin-3-yl] -4,5,6, 7-Tetrahydropyrazol [1,5-a] pyrimidine-6-carboxamide.

(Example 85) - 6- [6,6-Difluoro-2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2- methyl phenyl) pyridazin-3 (2H) -one.

(Example 98) 6- 6- {6- (tert-butylamino) methyl] -2- (2,4-difluoro phenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -benzamide 2- (2-methylphenyl) pyridazin-3 (2H) -one. (Example 107) 6- [1-acetyl-2 '- (4-fluoro phenyl) -4', 5'-dihydro spiro) [piperidine-4,6'-pyrazol [1,5-a] pyrimidin] - 3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one.

(Example 123) - 6 - [(5S) -2- (4-fluorophenyl) -5- (hydroxymethyl) [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one.

(Example 124) - 6 - [(5R) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-10 3-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one.

(Example 125) Ethyl 3- (4-fluorophenyl) -2- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -3-oxopropanoate. (Example 130) 6- (5-Isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-3-yl) -2- (2-methylphenyl) 15 pyridazin-3 (2H) -one.

[III] Test results

Table 1: Inhibition of TNF-α production in THP-I cells at 100 nM

<table> table see original document page 37 </column> </row> <table>

Test 2: Inhibition of hind paw swelling in rats with adjuvant-induced arthritis • [I] Test method Injection arthritis of 0.5 mg Mycobacterium tuberculosis (Difco Laboratories, Detroit, Michigan) in 50 µl paraffin was induced liquid on right hind paw 7-week-old female Lewis (Day 0). Normal untreated rats were used as negative controls. Animals were randomized and grouped (n> 5) for drug treatment based on an increase in left hind paw volume and body weight on day 15. Test compounds were suspended in vehicle (0.5% methyl cellulose) and administered orally once daily from 15th to 24th day by a water displacement method using a mouse plethysmometer (MK-550; Muromachi Kikai Co., Ltd., Tokyo, Japan).

[II] Test Compounds

(Example 3) 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (methyl phenyl ) -3 (2H) -pyridazinone

(Example 18) - 6- [2- (4-fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (methylphenyl) -3 (2H) -pyridazinone

(Example 37) 6- [2- (2,4-difluoro phenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - (methylphenyl) pyridazin-3 (2H) -one

(Example 63) - 6- [2 '- (4-fluorophenyl) -2,3,4', 5,5 ', 6-hexahydrospiro [pyran-4,6'-pyrazolo [1,5-a] pyrimidin-2-one 3'-yl] -2- (2-methylphenyl) -pyridazin-3 (2H) -one

(Example 86) - 6- [2'- (4-fluorophenyl) -4 ', 5'-dihydrospiro [1,3-dioxolane-2,6'-pyrazol [1,5-a] pyrimidin] -3'- yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one

(Example 100) - 6 - [(6R) -2- (4-fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( methyl 30 phenyl) pyridazin-3 (2H) -one

(Example 123) - 6 - [(5S) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] - 2- (methylphenyl) pyridazin-3 (2H) -one

(Example 124) - 6 - [(5S) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-2-one

3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one

(Example 132) 6- [2- (4-fluorophenyl) -6,6-dimethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (methylphenyl) pyridazin-3 (2H) -one [III] Test results

Table 2: Inhibition of hind paw swelling in 5 rats with adjuvant-induced arthritis.

<table> table see original document page 39 </column> </row> <table>

compound (i) and a salt thereof of the present invention are useful as inhibitors of cytokine production or transduction thereof, and by inhibiting MAPK p38a they possess pharmacological actions such as analgesic, antiinflammatory, anti arthritis mutilans action, or the like, and for the prevention and / or treatment of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, psoriasis, or the like. The pharmaceutical composition of the present invention may be used in the form of a pharmaceutical preparation, for example in a solid, semi-solid or liquid form containing the compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient mixed with an organic or inorganic carrier or excipient for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administration or for administration. The active ingredient may be composed, for example, with the usual non-toxic pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, insufflation powders, solutions, emulsions, suspensions, and any other suitable form. For use. In addition, when necessary, stabilizing agents, auxiliaries, thickening agents, coloring agents and perfumes may be used. A pharmaceutical composition includes compound (I) or a pharmaceutically acceptable salt thereof in an amount sufficient to produce the desired pharmaceutical effect mentioned above in response to the disease process or condition.

To apply the composition to a mammal (e.g., human, mouse, rat, pig, dog, cat, horse, ox, etc., especially human), it is preferable to apply the composition by intravenous, intramuscular, pulmonary or oral administration, or by insufflation. Although the dosage of therapeutically effective amount of compound (I) varies depending on the age and condition of each individual patient to be treated, for the prevention and / or treatment of the aforementioned diseases generally there will be a daily dose for intravenous administration. 0.01-100 mg of compound (I) per kg mammalian weight, for intramuscular administration, a daily dose of 0.1-100 mg of compound (I) per kg mammalian weight, and in In the case of oral administration, a daily dose of 0.5-100 mg of compound (I) per kg of a mammal's weight.

The following further explains the reactions for preparing compound (I) of the present invention with reference to Preparations and Examples. However, Preparations and Examples are given solely for the purpose of illustration of the present invention, and the invention should in no way be restricted to Preparations and Examples.

The abbreviations, symbols and terms used in the Preparations and Examples have the following meanings: AcOH = acetic acid; CDCl 3 = d-chloroform; CHCl3 = chloroform; CH 2 Cl 2 = dichloromethane; CH 3 CN = acetonitrile; EtOac or AcOEt = ethyl acetate; MeOH = methanol; EtOH = ethanol; PrOH = propanol; i-PrOH or IPA = isopropyl alcohol; BuOH = butanol; t- or tertiary-BuOH = t-butanol or tertiary-butanol; DME = 1,2-dimethoxy ethane; DMF = Δ, β-dimethylformamide, DMSO = 5 dimethyl sulfoxide; Et 3 N = triethylamine; IPE = diisopropyl ether; TFA = trifluoroacetic acid; THF = tetrahydrofuran; HOBt or HOBT = 1-hydroxy benzotriazole; EDCI or WSCD = 1-ethyl-3- [3 '- (dimethylamino) propyl] carbodiimide; Pd / C = palladium on carbon; MCPBA or mCPBA = 3-chloro peroxy benzene acid; min = minute (s); h = hour (s); rt = room temperature; conc = concentrate (a); aq = aqueous (a) (e.g. NaHCO3 aq solution); HCl = hydrochloric acid; CuBr2 = copper (II) bromide; Na 2 CO 3 = sodium carbonate; NaOH = sodium hydroxide; Na 2 SO 4 = sodium sulfate.

Preparation 1

To a solution of 3-chloro-6-methylpyridazine (51 g) and ethyl 4-fluorobenzoate (66.7 g) in THF (200 mL) was added dropwise bis (trimethyl silyl) amide. lithium (793 mL, 1.0 M in THF) over a period of min while maintaining the temperature below 15 ° C. After stirring for 30 min at room temperature, the mixture was cooled in an ice bath, and neutralized by the addition of cold water (250 mL) and 6 N HCl (175 mL). A solid was separated from the mixture and collected to give 2- (6-chloro-3-pyridazinyl) -1- (4-fluorophenyl) ethanone (36.6 g) as the first collection. The organic layer was separated from the mother liquor and washed with brine (150 mL, twice), dried over Na 2 SO 4, filtered and concentrated to form a suspension. This suspension was dissolved under reflux. To the solution was added hexane (600 mL) and the resulting suspension was aged for 1 hour with stirring at room temperature. The resulting solid was collected and washed with hexane (200 mL) to afford 2- (6-chloro-3-pyridazinyl) -1- (4-fluorophenyl) ethanone (51.3 g) as the second collection. Mass ESI (+) 251 (M + 1) 1H-NMR (300 MHz, DMSO-d6) δ 4.85 (2Η, s), 7.42 (2Η, t, J = 9 Hz), 7.78 (1Η, d, J = 8.7 Hz), 7.93 (1H, d, J = 8.7 Hz), 8.13-8.22 (2H, m)

Preparation 2

A mixture of 2- (6-chloro-3-pyridazinyl) -1- (4-fluorophenyl) ethanone (30.0 g) and sodium acetate (19.6 g) was stirred for 3 hours at 135 ° C. ) in AcOH (240 mL). After cooling to room temperature, cold water (400 mL) was added to this mixture. A separated solid was collected from the mixture, which was washed with water and vacuum dried to give 6- [2- (4-fluorophenyl) -2-oxoethyl] -3 (2H) -pyridazinone (17 g) as a solid. Grey.

Mass ESI (+) 251 (M + 1)

1H-NMR (300 MHz, DMS0-d6) δ 4.43 (2H, s), 6.87 (1H, d, J = 15 10 Hz), 7.36-7.43 (3H, m), 8 , 09-8.14 (2H, m)

Preparation 3

A mixture of 6- [2- (4-fluorophenyl) -2-oxoethyl] -3 (2H) -pyridazinone (4.8 g), ethylene glycol (9.6 mL) and hydrated toluene sulfonic acid (393 mg) in toluene (96 mL) was refluxed for 6 hours with azeotropic removal of water. After concentration, the residue was partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with brine, dried over Na 2 SO 4, filtered and evaporated in vacuo to give a solid.

The solid was triturated with hexane, collected and vacuum dried to afford 6- {[2- (4-fluorophenyl) -1,3-dioxolan-2-yl] methyl} -3 (2H) -pyridazinone (3.04 g ) as a white solid.

1H-NMR (200 MHz, DMS0-d6) δ 3.10 (2H, s), 3.67-3.74 (2H, 30 m), 3.89-3.97 (2H, m), 6, 76 (1H, d, J = 9.8 Hz), 7.11-7.20 (2H, m), 7.28 (1H, d, J = 9.8 Hz), 7.33-7.40 (2H, m), 12.76 (1H, s)

Preparation 4

A mixture of 6 - {[2- (4-fluorophenyl) -1,3-dioxolan-2-yl] methyl} -3 (2H) -pyridazinone (2.0 g), methyl benzene boronic acid (2 , 46 g), copper (II) acetate (263 mg) and pyridine (2.93 mL) in DMF (30 mL) for 14 hours at room temperature. The mixture was partitioned between EtOAc and H2O. The separated organic layer was washed with brine, dried over Na 2 SO 4, filtered and evaporated in vacuo. The residue was purified by column chromatography over SiO 2 (eluent: 1% to 8% methanol in dichloromethane) to give 6- {[2- (4-fluorophenyl) -1,3-dioxolan-2-yl] methyl} - 2- (2-methylphenyl) -3 (2H) -pyridazinone (2.17 g) as an amorphous solid.

1H-NMR (200 MHz, DMS0-d6) δ 1.83 (3H, s), 3.16 (2H, s), 3.70-3.84 (2H, m), 3.89-4, 04 (2H, m), 6.95-7.07 (2H, m), 7.09-7.23 (2H, m), 7.24-7.41 (5H, m), 7.46 ( 1H, d, J = 9.5 Hz)

Preparation 5

To a solution of 6 - {[2- (4-fluorophenyl) -1,3-dioxolan-2-15 yl] methyl} -2- (2-methylphenyl) -3 (2H) -pyridazinone (2.16 g) In THF (20 mL) conc. (2 mL) at room temperature. After stirring for 14 hours, the mixture was concentrated and partitioned between EtOAc and water. The organic layer was washed with 3% aqueous NaHCO 3 and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: 30% to 50% EtOAc in dichloromethane) to give 6- [2- (4-fluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) -3 (2H) -pyridazinone (1.64 g) as a light yellow waxy solid.

1H-NMR (200 MHz, DMS0-d6) δ 2.01 (3H, s), 4.51 (2H, s), 7.08 (1H, d, J = 9.6 Hz), 7.20- 7.47 (6H, m), 7.53 (1H, d, J = 9.6 Hz), 8.05-8.18 (2H, m)

Preparation 6

To a solution of 6- [2- (4-fluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) -3 (2H) -pyridazinone (500 mg) in AcOH (4 mL) was added pyridinium tribromide (595 mg) in portions at room temperature. After 3 h, the mixture was partitioned between EtOAc (8 mL) and water (16 mL). The separated organic layer was washed with water, 3% aqueous Na 2 S 2 O 3, 3% aqueous NaHCO 3 (twice) and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give 6- [1-bromo-2- (4-fluorophenyl ) -2-oxoethyl] -2- (2-methylphenyl) -3 (2H) -pyridazinone (566 mg) as a light yellow solid.

1H-NMR (200 MHz1 DMS0-d6) δ 1.89 (3H, s), 7.08 (1H, s), 7.15-7.48 (7H, m), 7.80 (1H, d, J = 9.7 Hz), 7.08-8.20 (2H, m)

Preparation 7

2- (6-Chloro-3-pyridazinyl) -1- (2,4-difluorophenyl) ethanone was obtained in a similar manner to that of Preparation 1.

1H-NMR (200 MHz, DMS0-d6) δ 4.74 (1.6H, d, J = 2.5 Hz), 6.25 (0.2H, s), 7.18-7.37 (1H , m), 7.39-7.56 (1H, m), 7.75-7.87 (1.2H, m), 7.88-8.11 (2H, m)

Preparation 8

6- [2- (2,4-Difluorophenyl) -2-oxoethyl-3 (2H) -pyridazinone was obtained in a similar manner to that of Preparation 2.

1H-NMR (200 MHz, DMS0-d6) δ 4.32 (2H, d, J = 3.0 Hz), 6.86 (1H, dd, J = 1.5, 10.0 Hz), 7, 27 (1H, dt, J = 2.5, 8.0 Hz), 7.38 (1H, d, J = 10.0 Hz), 7.40-7.53 (1H, m), 7.91-8 20 (1H, m), 12.91 (1H, brs)

Preparation 9

6 - {[2- (2,4-Difluorophenyl) -1,3-dioxolan-2-yl] methyl} -3 (2H) -pyridazinone was obtained in a similar manner to that of Preparation 3.

1H-NMR (200 MHz, DMS0-d6) δ 3.19 (2H, s), 3.72-3.87 (2H, m), 3.88-4.02 (2H, m), 6.76 (1H, d, J = 10.0 Hz), 7.01 (1H, dt, J = 2.5, 8.5 Hz), 7.17-7.42 (3H, m), 12.73 ( 1H, brs)

Preparation 10

At room temperature, a mixture of 6- {[2- (2,4-difluorophenyl) -1,3-dioxolan-2-yl] methyl} -3 (2H) -pyridazinone (8.00) was stirred for 2 days. g), 2-methyl benzene boronic acid (7.39 g), copper (II) acetate (988 mg) and pyridine (10.75 g) in THF (80 mL). The mixture was partitioned between EtOAc (120 mL) and 3% aqueous NaHCO 3 (160 mL). The organic layer was washed with 3% aqueous citric acid (2 times), 0.5 N NaOH (2 times) and brine, dried over Na 2 SO 4, filtered and evaporated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: EtOAc / hexane (w / w) = 1/1 to 2/1) to give 6 - {[2- (2,4-difluorophenyl) -1,3-dioxolan -2-yl] methyl} -2- (2-methyl 5-phenyl) -3 (2H) -pyridazinone (8.29 g) as a waxy solid. 1H-NMR (200 MHz, DMS0-d6) δ 1.81 (3H, s), 3.24 (2H, s), 3.74-3.90 (2H, m), 3.93-4.08 (2H, m), 6.92-7.09 (3H, m), 7.14-7.39 (5H, m), 7.47 (1H, d, J = 9.6 Hz) Preparation 11

6- [2- (2,4-Difluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) -3 (2H) -pyridazinone was obtained in a similar manner to that of

Preparation 5.

1H-NMR (200 MHz, DMS0-d6) δ 2.00 (3H, s), 4.40 (2H, d, J = 2.6 Hz), 7.08 (1H, d, J = 9.6 Hz), 7.19-7.58 (7H, m), 15 7.94-8.09 (1H, m)

Preparation 12

6- [1-Bromo-2- (2,4-difluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) -3 (2H) -pyridazinone was obtained in a similar manner to that of Preparation 6. 1H-NMR (200 MHz, DMS0-d6) δ 1.81 (3H, s), 6.76 (1H, s), 6.99-7.58 (7H, m), 7.80 (1H, d, J = 9.7 Hz), 7.98-8.14 (1H, m)

Preparation 13

A mixture of 4-methyl-4-25 phenylthio semicarbazide (544 mg), 3- (dimethyl aminomethyl) azetidine dihydrochloride (561 mg) and 1,8-diaza was stirred at 90 ° C for 3 hours. -bicyclo [5.4.0] undec-7-ene (0.94 mL) in acetonitrile (2 mL). The mixture was cooled to room temperature. Water (20 mL) was added to the mixture, and the mixture was washed with ether (20 mL). The organic layer was extracted with chloroform (40 mL, 2 times). The extracts were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was crystallized from diisopropyl ether to give 3 - [(dimethylamino) methyl] -1-azetidine carbothiohydrazide (248 mg) as a gray powder.

1H-NMR (500 MHz, CDCl3) δ 2.22 (s, 6H), 2.52 (d, 2H, J = 7.5 Hz), 2.80-2.85 (m, 1Η), 3.78 ( dd, 2Η, J = 5.5 Hz, 10.0 Hz), 4.20 (t, 2Η, J = 8.5 Hz), 6.39 (brs, 1Η).

Preparation 14

To a solution of 2-hydrazinoethanol (0.88 mL) in ethanol (85 mL) was added dropwise a solution of ethyl 3-isothiocyanate propionate (1.42 mL) in ethanol (8 mL) at room temperature. . The mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was purified by flash column chromatography (elution gradient: methanol / chloroform (w / w) = 0% to 6%) to give 3 - ({[1- (2-hydroxyethyl) hydrazino] carbonothiol} amino) ethyl propanoate (2.40 g) as colorless oil.

1H-NMR (500 MHz, CDCl3) δ 1.27 (3H, t, J = 7.5 Hz), 1.62 (1H, brs), 2.36 (1H, brs), 2.66 (2H , t, J = 5.9 Hz), 3.90 (2H, q, J = 6.0 Hz), 4.02-4.05 (2H, m), 4.08 (2H, s), 4 , 17 (2H, q, J = 7.3 Hz), 4.30 (2H, t, J = 5.0 Hz), 8.36 (1H, brs).

Preparation 15

6- [5- (Ethylamino) -3- (4-fluorophenyl) -1- (2-hydroxyethyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) -3 (2H) - pyridazinone in a similar manner to Example 1 below. Mass ESI (+) 434 (M + 1) 1 H-NMR (500 MHz, CDCl 3) δ 1.03 (3H, t, J = 6.7 Hz), 2.22 (3H, s), 3, 04-3.09 (2H, m), 3.83 (1H, brs), 4.01-4.03 (2H, m), 5.15 (1H, brs), 6.87 (1H, d, J = 9.8 Hz), 7.02 (1H, d, J = 9.8 Hz), 7.13 (2H, t, J = 8.2 Hz), 7.28-7.39 (4H, m), 7.48 (2H, dd, J = 8.8 Hz)

Preparation 16

6- [5- (Ethylamino) -3- (4-fluorophenyl) -1- (3-hydroxypropyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) -3 (2H) - pyridazinone in a manner similar to that of Example 1 below. Mass ESI (+) 448 (M + 1) 1H-NMR (500 MHz, CDCl3) δ 1.04 (3H, t, J = 7.8 Hz), 2.02-2.06 (2H, m), 2 , 23 (3H, s), 3.04-3.10 (2H, m), 3.55-3.63 (3Η, m), 4.24 (2Η, t, J = 6.8 Hz), 5.21 (1Η, brs), 7.14 (2Η, t, J = 8.4 Hz), 7.29-7.40 (4Η, m), 7.48 (2Η, dd, J = 5, 5.8 Hz). Preparation 17

3 - ({3- (4-fluorophenyl) -1- (2-hydroxyethyl) -4 - [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -1H ethyl-pyrazol-5-yl} amino) propanoate in a similar manner to Example 1 below. Mass ESI (+) 506 (M + 1) 1 H-NMR (500 MHz, CDCl 3) δ 1.19 (3H, t, J = 7.0 Hz), 2.24 (3H, s), 2, 36 (2H, t, 6.5 Hz), 3.31 (2H, dd, J = 6.4, 12.7 Hz), 3.65 (1H, t, J = 6.0 Hz), 4, 01-4.08 (4H, m), 4.20 (2H, t, J = 4.6 Hz), 5.18 (1H, t, J = 7.1 Hz), 6.89 (1H, d , J = 9.6 Hz), 7.01 (1H, d, J = 9.5 Hz), 7.13 (2H, 15 dd, J = 8.8, 8.8 Hz), 7.36- 7.70 (4H, m), 7.47 (2H, dd, J = 5.5, 8.7 Hz)

Preparation 18

3 - [{3- (4-fluorophenyl) -4- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -β-pyrazol-5-yl} ( Tertiary butyl 3-20 hydroxypropyl) amino] propanoate in a similar manner to Example 1 below. 1 H-NMR (500 MHz, CDCl 3) δ 1.42 (6H, s), 1.45 (3H, s) , 1.74-1.79 (2H, m), 2.10 (3H, s), 2.41 (2H, t, 7.5 Hz), 3.31 (2H, t, J = 6.9 Hz), 3.42 (2H, t, J = 7.5 Hz), 3.61 (2H, t, J = 5.3 Hz), 6.98 (1H, d, J = 9.6 Hz) 7.03 (2H, dd, J = 8.6 Hz), 7.17 (1H, d, J = 6.4 Hz), 7.28-7.42 (6H, m)

Preparation 19

N-Ethyl-1- (3-hydroxypropyl) hydrazine carbothioamide was obtained in a similar manner to Preparation 14.1H-NMR (500 MHz, CDCl3) δ 1.23 (3H, t, J = 7.3 Hz), 1.65-1.66 (1H, m), 3.55-3.64 (5H, m), 3.73 (2H, s), 4.28 (2H, 35 t, J = 5 9 Hz), 7.81 (1H, brs)

Preparation 20

G- [1-Bromo-2- (2,4-difluorophenyl) -2-oxoethyl] -3 (2Η) -pyridazinone was obtained in a similar manner to that of Preparation 6.

1H-NMR (200 MHz, DMS0-d6) δ 6.69 (1H, s), 6.93-7.11 (1H, m), 7.29 (1H, dt, J = 2.7, 8, 7 Hz), 7.38-7.53 (1H, m),

7.64 (1H, d, J = 9.9 Hz), 8.08 (1H, dt, J = 6.6, 8.9 Hz), 13.08-13.27 (1H, m)

Preparation 21

To a suspension of LiAlH4 (543 mg) in THF (20 mL) was added dropwise a solution of 4-10 (hydroxymethyl) tetrahydro-2H-thiopyran-4-carbonitrile (1.50 g) in THF (20 mL). ) at 0 ° C. The mixture was stirred for 1 h at the same temperature and the reaction was quenched by slowly adding H 2 O (0.5 mL), 10% aqueous NaOH (0.5 mL) and H 2 O (0.5 mL, 3 times) with ice cooling. After 10 min with stirring, insoluble materials were filtered off and the filter cake was washed with EtOAc. The filtrate was dried over MgSO 4, filtered and concentrated in vacuo to give [4- (aminomethyl) tetrahydro-2H-thiopyran-4-yl] methanol (1.30 g) as a light yellow oil.

Mass ESI (+) 162 (M + 1)

Preparation 22

To a mixture of [4- (aminomethyl) tetrahydro-2H-thiopyran-4-yl] methanol (1.20 g) in CH 2 Cl 2 (20 mL) and aqueous NaHCO 3 (1.25 g in 10 mL H 2 O) was added o-phenyl chloro-25 thiocarbonate (1.54 g) and the mixture was stirred vigorously for 30 min at room temperature. The organic layer was separated and the aqueous solution was extracted with CHCl 3. The combined organic layer was washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by column chromatography (eluent: Hexane / EtOAc = 1/1) to give o-phenyl {[4- (hydroxymethyl) tetrahydro-2H-thiopyran-4-yl] methyl} thiocarbamate (740 mg) as a colorless oil.

Mass ESI (+) 320 (M + Na)

Preparation 23

To a solution of o-phenyl {[4- (hydroxymethyl) tetrahydro-2H-1opyran-4-yl] methyl} thiocarbamate (740 mg) in i-PrOH (10 mL) was added monohydrate hydrazine (1.25 g ) and the mixture was stirred for 3 h at room temperature. The whole mixture was diluted with brine and CHCl 3. The aqueous layer was extracted with CHCl 3. The combined organic layer was washed with 0.5 M aqueous NaOH and brine, dried over MgSO 4, filtered and concentrated to give N - {[4- (hydroxymethyl) tetrahydro-2H-thiopyran-4-yl] methyl} hydrazine carbothioamide (300 mg) as a white solid. Mass ESI (+) 258 (M + Na)

Preparation 24

6- [5 - {[(2s) -2- (benzyloxy) -3-hydroxypropyl] amino} -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) ) pyridazin-3 (2H) -one in a manner similar to Example 1 below. Mass ESI (+) 526 (M + 1)

1H-NMR (CDCl3) δ 2.20 (3H, s), 3.40-3.65 (5H, m), 4.49 (2H, s), 6.00 (1H, br), 6.82 (1H, d, J = 9.9 Hz), 6.97 (1H, d, J = 9.9 Hz), 7.15-7.25 (4H, m), 7.25-7.36 ( 7H, m), 7.41-7.48 (2H, m).

Preparation 25

6- [5 - {[(2S) -2- (benzyloxy) -3-hydroxypropyl] amino} -3- (2,4-difluorophenyl) -1H-pyrazol-4-yl] -2- (2-Methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 544 (M + 1)

1H-NMR (CDCl3) δ 2.19 (3H, s), 3.39-3.67 (5H, m), 4.45-4.58 (2H, m), 6.12 (1H, br) 6.85 (1H, d, J = 9.9 Hz), 6.95-7.06 (2H, m), 6.95 (1H, dd, J = 1.4, 9.9 Hz), 7.20-7.26 (2H, m), 7.26-7.37 (7H, m), 7.41-7.51 (1H, m)

Preparation 26

6- [5- {[(2R) -2- (benzyloxy) -3-hydroxypropyl] amino} -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2- methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 526 (M + 1)

1H-NMR (CDCl3) δ 2.20 (3H, s), 3.41-3.64 (5H, m), 4.49 (2Η, s), 6.00 (1Η, t, J = 6, 2 Hz), 6.81 (1Η, d, J = 9.9 Hz), 7.16-7.24 (4Η, m), 7.25-7.36 (7H, m), 7.42- 7.48 (2H, m)

Preparation 27

6- [5- {[(2R) -2- (benzyloxy) -3-hydroxypropyl] amino} -3- (2,4-difluorophenyl) -1H-pyrazol-4-yl] -2- (2-Methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 544 (M + 1) 1 H-NMR (CDCl 3) δ 2.18 (3H, s), 3.39-3.67 (5H, m), 4.42-4.53 ( 2H, m), 6.08 (1H, br), 6.85 (1H, d, J = 10.1 Hz), 6.93-7.03 (2H, m), 6.94 (1H, dd) , J = 1.4, 10.1 Hz), 7.18-7.23 (2H, m), 7.24-7.35 (7H, m), 7.39-7.47 (1H, m )

Preparation 2 8

6 - [3- (2,4-Difluorophenyl) -5 - {[(2S) -2- (2,2-dimethylpropoxy) -3-hydroxypropyl] amino} -1H-pyrazole-4 was obtained. - yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 544 (M + 1) 1H-NMR (CDCl3) δ 2.18 (3H, s), 3.39-3.67 (5H, m), 4.42-4.53 (2H , m), 6.08 (1H, br), 6.85 (1H, d, J = 10.1 Hz), 6.93-7.03 (2H, m), 6.94 (1H, dd, J = 1.4, 10.1 Hz), 7.18-7.23 (2H, m), 7.24-7.35 (7H, m), 7.39-7.47 (1H, m)

Preparation 2 9

3 - ({3- (2,4-difluorophenyl) -4- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -1H-pyrazol-5-yl } amino) -2- (hydroxymethyl) propanoate of ethyl in a similar manner to Example 1 below. 1H-NMR (CDCl3) δ 1.11 (3H, d, J = 6.9 Hz), 2.20 (3H, s), 2.66-2.70 (1H, m), 3.65-3 68 (2H, m), 3.76-3.82 (2H, m), 3.92-4.03 (2H, m), 6.03 (1H, brs), 6.85 (1H, d , J = 9.2 Hz), 6.92-7.01 (3H, m), 7.29-7.43 (5H, m).

Preparation 30

3- ({3- (4-fluorophenyl) -4- [1- (2-methylphenyl) -6-35 oxo-1,6-dihydropyridazin-3-yl] -1H-pyrazol-5-yl} amino) -2- (hydroxymethyl) propanoate ethyl in a similar manner to Example 1 below. 1 H-NMR (CDCl 3) δ 1.12 (3 (, d, J = 7.2 Hz), 2.22 (3Η, s), 2.69-2.73 (1H, m), 3.66-3.72 (2H, m), 3.77-3.83 (2H, m), 3.91-4 , 04 (2H, m), 5.98 (1H, brs), 6.82 (1H, d, J = 10.1 Hz), 7.34-7.38 (4H, m), 7.45 ( 2H, dd, J = 5.4, 8.5 Hz).

Preparation 31

3- ({3- (2,4-Difluorophenyl) -4- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -1H-pyrazol-5-yl } amino) butanoate in a manner similar to Example 1 below. 1H-NMR (CDCl3) δ 1.18-1.23 (6H, m), 2.22 (3H, s), 2.41-2.46 (1H, m), 2.59-2.64 ( 1H, m), 3.98-4.02 (1H, m), 4.10 (2H, q, J = 7.3 Hz), 6.07 (1H, brs), 6.86 (1H, d , J = 9.2 Hz), 6.95-7.06 (3H, m), 7.30-7.38 (4H, m), 7.50 (1H, dd, 7.8, 16.5 Hz) Preparation 32 6- [5- {[3-tertiarybutoxy-2- (hydroxymethyl) propyl] amino} -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. 1 H-NMR (CDCl 3) δ 1.11 (9H, s), 1.86-1.90 (1H, m), 2.20 (3H, s), 3.36 (2H, d, J = 5 9 Hz), 3.40 (2H, dd, J = 6.4, 6.4 Hz), 3.61 (2H, ddd, J = 4.1, 11.0, 28.0 Hz), 5 , 98 (1H, brs), 6.81 (1H, d, J = 9.7 Hz), 6.98 (1H, d, J = 10.2 Hz), 7.17 (2H, dd, J = 8.7, 8.7 Hz), 7.34-7.38 (4H, m), 7.46 25 (2H, dd, J = 5.0, 8.2 Hz) Preparation 33 Obtained 6- [ 3- (2,4-difluorophenyl) -5 - ({[1- (hydroxymethyl) cyclopropyl] methyl} amino) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) - according to a manner similar to that of Example 1 below. Mass ESI (+) 464 (M + 1) 1 H NMR (CDCl 3) δ 0.33 (4H, m), 2.22 (3H, s), 3.22 (2H, s), 3.35 ( 2H, brs), 6.24 (1H, brs), 6.86 (1H, d, J = 9.5 Hz), 6.95-7.03 (3H, m), 7.33-7.39 (4H, m), 7.46 (1H, dd, 35 J = 8.2, 14.5 Hz) Preparation 34

6- [3- (4-Fluorophenyl) -5 - ({[1- (hydroxymethyl) cyclopropyl] methyl} amino) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a manner similar to Example 1 below. Mass ESI (+) 446 (M + 1) 1H-NMR (CDCl3) δ 0.33-0.38 (4H, m), 2.24 (3H, s), 3.23 (2H, d, J = 5.9 Hz), 3.32 (2H, brs), 6.11 (1H, brs), 6.83 (1H, d, J = 9.6 Hz), 6.99 (1H, d, J = 9.6 Hz), 7.18 (2H, dd, J = 8.5, 8.5 Hz), 7.33-7.39 (4H, m), 7.45 (2H, dd, J = 5.1, 8.8 Hz)

Preparation 35

6- [5 - ({[1- (hydroxymethyl) cyclopropyl] methyl} amino) -3- (3-methylphenyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-2-one 3 (2H) -one in a manner similar to Example 1 below.

Mass ESI (+) 442 (M + 1)

1H-NMR (CDCl3) δ 0.33-0.37 (4H, m), 2.24 (3H, s), 2.42 (3H, s), 3.24 (2H, brs), 3.31 (2H, brs), 6.09 (1H, brs), 6.81 (1H, d, J = 10.2 Hz), 7.05 (1H, d, J = 10.5 Hz), 7.24 -20 7.40 (8H, m)

Preparation 36

6- [3- (2,4-Difluorophenyl) -5 - ({[1- (hydroxymethyl) cyclobutyl] methyl Jaraino) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-2-one 3 (2H) -one in a manner similar to Example 1 below.

Mass ESI (+) 478 (M + 1)

1H-NMR (CDCl3) δ 1.56-1.69 (4H, m), 1.82-1.88 (2H, m), 2.22 (3H, s), 3.36 (2H, d, J = 6.5 Hz), 3.47 (2H, s), 6.24 (1H, brs), 6.85 (1H, d, J = 10.1 Hz), 6.94-7.05 ( 3H, m), 7.33-7.40 (4H, m), 7.46 (1H, dd, J = 8.2, 14.7 Hz)

Preparation 37

6- [3- (4-Fluorophenyl) -5- ({[1- (hydroxymethyl) cyclobutyl] methyl} amino) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a manner similar to Example 1 below.

Mass ESI (+) 460 (M + 1)

1H-NMR (CDCl3) δ 1.55-1.70 (4H, m), 1.83-1.89 (2H, m), 2.23 (3Η, s), 3.37 (2Η, d, J = 6.5 Hz), 3.45 (2Η, s), 6.11 (1Η, brs), 6.82 (1H, d, J = 10.2 Hz), 6.99 (1H, d, J = 9.9 Hz), 7.19 (2H, dd, J = 8.3, 8.3 Hz), 7.34-7.39 (4H, m), 7.45 (1H, dd, J = 5.0, 8.7 Hz)

Preparation 38

6- [3- (2,4-Difluorophenyl) -5 - ({[3-hydroxymethyl) -1-isopropyl-azetidinin-3-yl] methyl} amino) -1H-pyrazol-4-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one in a manner similar to that of Example 1 and Example 123, successively mentioned below.

1H-NMR (CDCl3) δ 0.92 (6H, d, J = 6.2 Hz), 2.20 (3H, s), 2.39-2.45 (1H, m), 2.98 (2H , d, J = 8.2 Hz), 3.01 (2H, d, J = 8.4 Hz), 3.56 (2H, d, J = 6.4 Hz), 3.57 (2H, s ), 6.25 (1H, brs), 6.85 (1H, d, J = 10.1 Hz), 6.93-7.02 (3H, m), 7.31-7.38 (4H, m), 7.45 (1H, dd, J = 8.6, 15.1 Hz)

Preparation 39

6- {3- (2,4-difluorophenyl) -5 - [(2-hydroxy-1,1-dimethyl-ethyl) amino] -1H-pyrazol-4-yl} -2- (2-methylphenyl) ) pyridazin-3 (2H) -one according to a manner similar to Example 1 below.

Mass ESI (+) 452 (M + 1)

1H-NMR (CDCl3) δ 1.11 (6H, s), 2.21 (3H, s), 3.55 (2H, m), 6.35 (1H, brs), 6.84 (1H, d , J = 9.5 Hz), 6.92-6.98 (3H, m), 7.31-7.37 (4H, m), 7.42 (1H, dd, J = 7.8, 14 , 25 Hz)

Preparation 40

6- [3- (2,4-Difluorophenyl) -5 - {[(2S) -2-hydroxypropyl] amino} -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a manner similar to Example 1 below.

1H-NMR (CDCl3) δ 1.11 (6H, s), 2.21 (3H, s), 3.55 (2H, m), 6.35 (1H, brs), 6.84 (1H, d , J = 9.5 Hz), 6.92-6.98 (3H, m), 7.31-7.37 (4H, m), 7.42 (1H, dd, J = 7.8, 14 , 3 Hz)

Preparation 41

6- [3- (2,4-Difluorophenyl) -5 - {[(2R) -2-hydroxypropyl] amino} -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. 1 H-NMR (CDCl 3) δ 1.09 (3H, d, J = 6.0 Hz), 2.20 (3H, s), 3.10-3.17 (1H, m), 3.22-3.27 (1H, m), 3.88-3.94 (1H, m), 5 6.16 (1H, brs), 6 , 85 (1H, d, J = 9.6 Hz), 6.92-6.99 (3H, m), 7.32-7.37 (4H, m), 7.43 (1H, dd, J = 8.3, 15.6 Hz)

Preparation 42

6- {3- (2,4-Difluorophenyl) -5 - [(2S) -2- (hydroxymethyl] pyrrolidin-1-yl] -1H-pyrazol-4-yl} -2- (2-10 methylphenyl) pyridazin-3 (2H) -one in a manner similar to that of Example 1 below Mass Spec (+) 464 (M + 1)

1H-NMR (CDCl3) δ 1.68-1.74 (1H, m), 1.81-1.91 (2H, m), 2.02-2.10 (1H, m), 2.07 ( 3H, s), 3.08 (1H, dd, J = 6.9, 16.5 Hz), 3.40 (1H, dd, J = 6.9, 15.1 Hz), 3.64 (1H , dd, J = 6.4, 11.0 Hz), 3.75 (1H, dd, J = 3.2, 11.0 Hz), 3.94-3.99 (1H, m), 6, 82-6.91 (2H, m), 6.96 (1H, d, J = 9.6 Hz), 7.07-7.13 (1H, m), 7.27-7.35 (4H, m), 7.39 (1H, dd, J = 8.4, 14.7 Hz)

Preparation 43

6- [3- (4-Fluorophenyl) -5 - {[(IR) -2-hydroxymethyl] amino} -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin -3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 420 (M + 1) 1H-NMR (CDCl3) δ 1.04 (3H, d, J = 6 .0 Hz), 2.23 (3H, s), 3.36-3.45 (1H, m), 3.65 (2H, d, J = 8.2 Hz), 6.01 (1H, brs ), 6.83 (1H, d, J = 9.6 Hz), 6.98 (1H, d, J = 9.6 Hz), 7.14 (2H, dd, J = 8.7 Hz, J = 8.7 Hz), 7.28-7.42 (4H, m), 7.45 (2H, dd, J = 5.5, J = 8.7 Hz). Preparation 44

6- [3- (4-fluorophenyl) -5- ({[4- (hydroxymethyl) tetrahydro-2H-thiopyran-4-yl] methyl} amino) -1H-pyrazol-4-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below.

Mass ESI (+) 506 (M + 1) 1H-NMR (CDCl3) δ 1.42 (4Η, br), 2.10 (3Η, s), 2.41-2.44 (4H, m), 3.06 (2Η, d, J = 5 Hz), 3.12 (2Η, d, J = 5 Hz), 4.16 (2H, t, J = 6 Hz), 5.57 (1H, br) 6.92 (1H, m), 7.03 (1H, m), 7.34-7.40 (6H, m), 7.53 (2H, m), 12.29 (1H, s)

Preparation 45

6- [5- ({[1- (bromomethyl) cyclohexyl] methyl} amino) -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin -3 (2H) -one in a similar manner to Example 1 below.

Mass ESI (+) 550 (M + 1)

1H-NMR (CDCl3) δ 1.12-1.38 (10H, m), 2.09 (3H, s), 3.11-3.19 (4H, m), 6.92 (1H, d, J = 10.0 Hz), 7.01 (1H, d, J = 10.0 Hz), 7.32-7.41 (6H, m), 7.52-7.58 (2H, m)

Preparation 46

6 - [3- (4-Fluorophenyl) -5 - ({[4- (hydroxymethyl) tetrahydro-2H-pyran-4-yl] methyl} amino) -1H-pyrazol-4-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one according to a similar manner to Example 1 below.

Mass ESI (+) 490 (M + 1)

1H-NMR (CDCl3) δ 1.48-1.56 (2H, m), 1.68-1.79 (2H, m), 2.01 (2H, t, J = 6 Hz), 2.25 (3H, s), 3.07-3.22 (2H, m), 3.60-3.75 (2H, m), 4.18 (2H, t, J = 6 Hz), 6.79- 6.82 (1H, m), 6.83 (1H, d, J = 10 Hz), 7.06 (1H, d, J = 10 Hz), 7.14-7.19 (2H, m), 7.35-7.39 (4H, m), 7.48-7.53 (2H, m)

Preparation 47

6- {5 - [({4- (benzyloxy) methyl] -1,1-dioxy-tetrahydro-2H-thiopyran-4-yl} methyl) amino] -3- (4-fluorophenyl ) -1H-pyrazol-4-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one according to a similar manner to Example 1 below.

Mass ESI (+) 628 (M + 1)

1H-NMR (CDCl3) δ 1.83-1.96 (4H, m), 2.18 (3H, s), 2.78-2.84 (2H, m), 3.04-3.08 ( M), 3.08 (2H, s), 3.50 (2H, d, J = 6 Hz), 4.11 (2H, s), 6.35 (1H, br), 6.83 ( 1H, d, J = 10 Hz), 6.92 (1H, d, J = 10 Hz), 7.13-7.17 (4H, m), 7.27-7.43 (9H, m) Preparation 48

6- [5 - {[(IS) -1 ({[tertiary butyl (diphenyl) silyl] oxy} methyl) -3-hydroxypropyl] methylphenyl) pyridazin-3 (2H) -one was obtained in a similar manner to of Example 1 below. 1H-NMR (CDCl3) δ 0.80 (9H, s), 1.52-1.62 (1H, m), 1.70-1.83 (1H, m), 2.07 (3H, s) , 3.46-3.86 (5H, m), 4.46 (1H, brs), 5.53 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.03 ( 1H, d, J = 10 Hz), 7.24-7.56 (18H, m), 12.27 (1H, brs)

Preparation 49

6- [5- {[(IR) -1 - ({[tertiary butyl (diphenyl) silyl] oxy} methyl) -3-hydroxypropyl] amino} -3- (4-fluorophenyl) -1H-pyrazol-4 -yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. 1H-NMR (DMS0-d6) δ 0.80 (9H, s), 1.52-1.62 (1H, m), 1.70-1.83 (1H, m), 2.07 (3H, s), 3.46-3.86 (5H, m), 4.46 (1H, brs), 5.53 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7, 03 (1H, d, J = 10 Hz), 7.24-7.56 (18H, m), 12.27 (1H, brs)

Preparation 50

4- [{3- (4-fluorophenyl) -4] - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -1H-pyrazol-5-yl} tert-butyl amino] methyl] -4- (hydroxymethyl) piperidine-1-carboxylate according to a manner similar to that of Example 1 below. Mass ESI (+) 611 (M + Na)

Preparation 51

6- [3- (4-Fluorophenyl) -5- {[4- (2-hydroxyethyl) tetrahydro-2H-pyran-4-yl] amino} -1H-pyrazol-4-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below.

Mass ESI (+) 472 (M + 1)

1H-NMR (CDCl3) δ 1.52-1.64 (2H, m), 1.80-1.90 (2H, m), 1.83-1.87 (2H, m), 2.24 ( 3H, s), 3.09-3.28 (2H, m), 3.38-3.50 (2H, m), 3.71 (2H, t, J = 6 Hz), 6.85 (1H , d, J = 10 Hz), 6.97 (1H, d, J = 10 Hz), 7.18-7.25 (2H, m), 7.32-amino} -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-7.41 (4Η, m), 7.44-7.48 (2Η, m)

Preparation 52

6- {3- (4-Fluorophenyl) -5- [3- (hydroxy-2,2-dimethylpropyl) amino] -1H-pyrazol-4-yl} -2- (2-methylphenyl) pyridazin-2-one 3 (2H) -one in a manner similar to Example 1 below. Mass ESI (+) 448 (M + 1)

1H-NMR (CDCl3) δ 0.62 (6H, s), 2.10 (3H, s), 2.98-3.00 (4H, m), 4.59 (1H, t, J = 6 Hz ), 6.91-7.04 (2H, m), 7.34-7.39 (6H, m), 7.53 (2H, m)

Preparation 53

6- {3- (4-fluorophenyl) -5 - [(2-hydroxyethyl) amino] -1H-pyrazol-4-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one according to a manner similar to that of Example 1 below.

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.45-3.52 (2H, m), 3.72-3.78 (2H, m), 6.82 (1H, d, J = 9.5 Hz), 6.89 (1H, d, J = 10.0 Hz), 7.06-7.17 (2H, m), 7.31-7.42 (8H, m) Preparation 54

6- [5 - {[(1S) -2- (benzyloxy) -1- (hydroxymethyl) ethyl] amino} -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 548 (M + Na)

1H-NMR (CDCl3) δ 2.18 (3H, s), 3.27-4.41 (7H, m), 6.65-7.63 (15H, m)

Preparation 55

6- [5- {[(1R) -2- (benzyloxy) -1- (hydroxymethyl) ethyl] amino} -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below. Mass ESI (+) 548 (M + Na)

1H-NMR (CDCl3) δ 2.20 (3H, s), 3.50 (2H, m), 3.70 (2H, m), 3.93 (1H, brs), 4.22 (2H, s) ), 6.85 (1H, d), 7.08 (3H, m), 7.19-7.43 (11H, m)

Preparation 56

(2S) - ({3- (4-Fluorophenyl) -4- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyrazin-3-yl] -1H-pyrazolacetate) 5-yl} amino) -3-methyl butyl in a similar manner to Example 1 below. Mass ESI (+) 490 (M + 1) δ 1H NMR (CDCl3) δ 0.54-0.66 (3H, m), 0.80-0.90 (3H, m), 1.78- 1.88 (1H, m), 1.98 (3H, s), 2.22 (3H, s), 3.46-3.64 (1H, m), 3.93-4.02 (1H, m), 4.18-3.25 (1H, m), 6.13-6.31 (1H, m), 6.82 (1H, d, J = 9.5 Hz), 7.02 (1H , d, J = 9.5 Hz), 7.20 (2H, dd, J = 8.5 Hz, J = 8.5 Hz), 7.30-7.39 (4H, 10 m), 7, 49 (2H, dd, J = 5.5, J = 8.5 Hz)

Preparation 57

6- {5 - [(3-Bromo-2,2-difluoropropyl) amino] -3- (4-fluorophenyl) -1H-pyrazol-4-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one in a manner similar to Example 1 below.

1H-NMR (CDCl3) δ 2.23 (3H, s), 3.55 (2H, t, J = 13.5 Hz), 3.89 (2H, J = 13.0 Hz, J = 6.5 Hz), 5.98 (1H, m), 6.85 (1H, d, J = 9.5 Hz), 6.98 (1H, d, J = 9.5 Hz), 7.24 (2H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.31-7.42 (4H, m), 7.46 (2H, dd, J = 20 5.5 Hz, J = 9, 0 Hz), 9.09 (1H, brs) Preparation 58

6- [5 - ({[2- (bromomethyl) -1,3-dioxolan-2-

yl] methyl} amino) -3- (4-fluorophenyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1 below .

1H-NMR (CDCl3) δ 2.23 (3H, s), 3.39 (2H, s), 3.54-3.66 (2H, m), 3.69-3.89 (2H, m) , 3.91-4.05 (2H, m), 6.07 (1H, brs), 6.83 (1H, d, J = 10.0 Hz), 6.99 (1H, d, J = 10 .0 Hz), 7.20 (2H, dd, J = 9.0 Hz, J = 9.0 Hz), 7.33-7.43 (4H, m), 7.47 (2H, dd, J = 5.5 Hz, J = 9.0 Hz) Preparation 59

6- {3- (2,4-Difluorophenyl) -5 - [(3-hydroxy-1-methyl propyl) amino] -1H-pyrazol-4-yl} -2- (2-methylphenyl) pyridazin-2-one 3 (2H) -one in a manner similar to Example 10 below.

1H-NMR (CDCl3) δ 1.09 (3H, d, J = 5.5 Hz), 1.71-1.77 (2H, m), 2.23 (3H, s), 3.51-3 , 55 (1H, m), 3.59-3.66 (2H, m), 5.99 (1H, brs), 6.84 (1H, d, J = 10.1 Hz), 6.90-6 , 98 (3Η, m), 7.27-7.43 (5H, m)

Preparation 60

6- [3- (4-Fluorophenyl) -5 - ({[4- (hydroxymethyl) -1,1-5 tetrahydro-2H-thiopyran-4-yl] methyl} amino) -1H-pyrazol-2-one 4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one according to a similar manner to Example 95 below.

Mass ESI (+) 538 (M + 1)

1H-NMR (CDCl3) δ 1.70 (4H, m), 2.10 (3H, s), 2.90-3.02 (4H, m), 3.16 (2H, s), 3.23 (2H, d, J = 6 Hz), 6.94 (1H, d, J = 10 Hz), 7.06 (1H, d, J = 10 Hz), 7.30-7.40 (6H, m ), 7.51-7.55 (2H, m)

Preparation 61

4 - ({3- (4-fluorophenyl) -4 - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -β-pyrazol-5-yl} amino) Benzyl 4- (2-hydroxyethyl) piperidine-1-carboxylate according to a manner similar to Example 123 below.

1H-NMR (DMS0-d6) δ 1.36 (2H, t), 1.91 (3H, brs), 2.07 (3H, s), 2.67 (2H, brs), 3.51 (2H , m), 4.21 (1H, t), 5.03 (2H, brs), 5.82 (1H, s), 6.55 (1H, s), 6.94 (1H, d), 7 .03 (1H, d), 7.25-7.46 (9H, m), 7.57 (2H, m), 7.69 (4H, m)

Example 1

A mixture of 6- [1-bromo-2- (2,4-difluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) -3 (2H) -pyridazinone (210 mg), 3 - [(dimethylamino) methyl] -1-azetidine carbothiohydrazide (113 mg) in glacial acetic acid (1.5 mL) was heated at 55-60 ° C for 1.5 h. The mixture was poured into water (20 mL), neutralized with sodium hydrogen carbonate and extracted with ethyl acetate (30 mL). The extract was concentrated under reduced pressure. The residue was purified by SiO 2 flash column chromatography (eluent: 0% to 4% methanol in chloroform) to give 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4- 5,6,7-Tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2Η) -pyridazinone (167 mg) as a yellow amorphous solid.

Mass ESI (+) 477 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.21 (3H, s), 2.24 (6H, s), 2.26-2.43 (3H, m), 3.09 (1H, t, J = 8.9 Hz), 3.48 (1H, d, J = 12.3 Hz), 3.82 (1H, dd, J = 8.1 Hz, 12.4 Hz), 4.27 (1H, dd, J = 5.6 Hz, 12.4 Hz), 5.90 (1H, brs), 6.83 (1H, d, J = 9.6 Hz), 6.92-6.97 (2H, m), 7.00-7.04 (1H, m), 7.34-7.38 (4H, m), 7.55 (1H, dd, J = 8.1 Hz, 14.7 Hz)

Example 2

A mixture of 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone (48 mg) and 2,3-dichloro-5,6-di-cyano-p-benzoquinone (23 mg) in dioxane (1 mL) was stirred at room temperature. overnight. Water (10 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (15 mL). The extract was concentrated under reduced pressure. The residue was purified by SiO 2 flash column chromatography (eluent: ethyl acetate to 4% methanol in chloroform) to give 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] pyrazol [ 1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone (22 mg) as a yellow oil. Mass ESI (+) 473 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.05 (3H, s), 2.33 (6H, s), 3.55 (2H, s), 6.67 (1H, t, J = 10.2 Hz), 6.87 (1H, t, J = 8.2 Hz), 7.01 (1H, d, J = 7.8 Hz), 7.14-7.19 (1H, d, J = 9 , 6 Hz), 7.52 (2H, d, J = 6.9 Hz), 8.31 (2H, d, J = 9.5 Hz), 8.64 (2H, d, J = 6.9 Hz)

Example 3

6- [2- (4-Fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 432 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 1.69 (1H, brs), 2.23 (3H, s), 2.40-2.50 (1Η, m), 3.20-3.30 (1Η , m), 3.46-5.30 (1Η, m), 3.72-3.78 (2Η, m), 3.98 (1Η, dd, J = 7.3 Hz, 13.0 Hz) , 4.25 (1Η, dd, J = 5.2 Hz, 13.0 Hz), 5.81 (1Η, brs), 6.81 (1H, d, J = 9.5 Hz), 7.02 (1Η, d, J = 9.5 Hz), 7.15 (2Η, dd, J = 8.2 Hz, 8.5 Hz), 7.31-7.41 (4Η, m), 7.50 (2H, dd, J = 5.6 Hz, 8.2 Hz)

Example 4

To a 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) suspension ) -3 (2H) -pyridazinone (0.216 mg) in tetrahydrofuran (2 mL) was added imidazole (85 mg) and triphenyl phosphine (197 mg) and the suspension was stirred at room temperature for 5 minutes. To the suspension was added dropwise a solution of iodine (190 mg) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 1.5 h. To the reaction mixture was added EtOAc (50 mL), and the solution was washed successively with 3% aqueous Na 2 S 2 O 3 (20 mL), saturated aqueous NaHCO 3 solution (20 mL) and brine (20 mL). The organic layer was dried over anhydrous MgSO4 and the insoluble substance was filtered off. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (elution gradient: hexane / EtOAc (w / w) 0% to 100%) to give 6- [2- (4-fluorophenyl) -6- (methyl iodine) -4, 5,6,7-Tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone (0.211 g) as yellow solid. 1H-NMR (500 MHz, CDCl3) δ 2.23 (3H, s), 2.44-2.52 (1H, m), 3.22-3.26 (1H, m), 3.26 (2H , d, J = 6.9 Hz), 3.51-3.57 (1H, m), 3.96 (1H, dd, J = 7.6 Hz, 13.0 Hz), 4.34 (1H , dd, J = 5.1 Hz, 13.0 Hz), 5.84 (1H, brs), 6.81 (1H, d, J = 9.2 Hz), 7.02 (1H, d, J = 9.2 Hz), 7.16 (2H, dd, J = 8.2 Hz, 8.5 Hz), 7.32-7.42 (4H, m), 7.50 (2H, dd, J = 5.0 Hz, 8.2 Hz)

Example 5

To a suspension of 6- [2- (4-fluorophenyl) -6- (methyl iodine) - {4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl}] -2- ( 2-methylphenyl)] -3 (2H) -pyridazinone (50 mg) in CH 3 CN (1 mL) was added 4-dimethylamino piperidine (36 mg) and K 2 CO 3 (25.6 mg), and the suspension was stirred at 80 ° C. ° C for 2.5 h. 4-Dimethylamino piperidine (36 mg) was added to the suspension, and the suspension stirred for a further 8 h. To the reaction mixture was added EtOAc (30 mL), and the solution was extracted with 10% citric acid (20 mL, 2 times). The extracts were combined and the solution was alkalized with NaHCO3. The suspension was extracted with EtOAc (20 mL, 3 times), and the organic layers were combined. The solution was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in vacuo. 4 M HCl in EtOAc (2 mL) was added to the residue to give 6- [6- {[4- (dimethylamino) -1-piperidinyl] methyl} -2- (4-fluorophenyl) -4,5 dihydrochloride, 6,7-Tetrahydropyrazolo [1,5-a] pyrimidin-3-yl}] -2- (2-methylphenyl)] -3 (2H) -pyridazinone (25 mg).

Mass ESI (+) 542 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.09 (3H, s), 2.16-2.32 (4H, m), 2.68-2.81 (7H, m), 2.90-3 .02 (2H, m), 3.10-3.22 (3H, m), 3.26 (2H, d, J = 6.9 Hz), 3.47-3.54 (1H, m), 3.62-4.07 (4H, m), 6.10 (1H, brs), 6.95 (1H, d, J = 9.5 Hz), 7.10 (1H, d, J = 9, 5 Hz), 7.24 (2H, dd, J = 5.5 Hz, 8.5 Hz), 7.31-7.40 (4H, m), 7.49 (2H, dd, J = 5, 5 Hz, 8.5 Hz), 10.8 (1H, brs), 11.1 (1H, brs)

Example 6

A mixture of 6- [5- (ethylamino) -3- (4-fluorophenyl) -1- (2-hydroxyethyl) -1H-pyrazol-4-yl] -2- (2-methylphenyl) -3 (2H) - pyridazinone (858 mg), imidazole (337 mg, 4.95 mmol) and triphenyl phosphine (779 mg) in tetrahydrofuran (5.0 mL) were stirred at room temperature for 3 h. A solution of iodine (754 mg) in THF (5.0 mL) was added dropwise to the mixture. The mixture was stirred overnight. THF (4.0 mL), imidazole (236 mg) and triphenyl phosphine (545 mg) were added to the mixture.

The mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise a solution of iodine (754 mg) in THF (4.0 mL) at room temperature, and the mixture was stirred for 6 h. The resulting precipitate was removed by filtration. EtOAc (50 mL) was added to the filtrate. The mixture was washed successively with 5% aqueous Na 2 S 2 O 3 (30 mL), 5% aqueous NaHCO 3 solution (30 mL) and brine (30 mL). The organic layer was concentrated under reduced pressure. The residue was purified by flash column chromatography (elution gradient: EtOAc / hexane = 50% to 85%). Isopropyl ether was added to the crystalline residue, and the solid was filtered off. To the solid was added 10% HCl (100 mL) and EtOAc (50 mL). The aqueous layer was separated, washed with Et 2 O and neutralized with NaOH. The mixture was extracted with EtOAc (100 mL). The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure. Hexane was added to the crystalline residue, and the solid was filtered off to give 6- [1-ethyl-6- (4-fluorophenyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-2-one. 7-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone as light yellow prisms (460 mg). Mass ESI (+) 416 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 0.97 (3H, t, J = 6.8 Hz), 2.20 (3H, s), 3.27 (2H, q, J = 6.9 Hz) , 3.81 (2H, t, J = 8.6 Hz), 4.20 (2H, t, J = 8.2 Hz), 6.86 (1H, d, J = 9.7 Hz), 6 , 97 (1H, d, J = 9.7 Hz), 7.08 (2H, dd, J = 8.7 Hz, 8.7 Hz), 7.26-7.36 (4H, m), 7 , 46 (2H, dd, J = 5.5 Hz, 8.7 Hz)

Example 7

A mixture of 3 - [{3- (4-fluorophenyl) -4- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -1H-pyrazol-5-yl} ( Tertiary butyl 3-hydroxypropyl) amino] propanoate (175 mg), triphenyl phosphine (126 mg) and diethyl azo dicarboxylate (75 µL) in THF (6 mL) was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (elution gradient: EtOAc / hexane = 20% to 95%) to give 3- [2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6 tertiarybutyl-oxo-1,6-dihydro-3-pyridazinyl] -6,7-dihydropyrazolo [1,5-a] pyrimidin-4 (5H) -yl] propanoate (153 mg) as yellow amorphous solid.

1H-NMR (500 MHz, CDCl3) δ 1.39 (9H, s), 2.16 (3H, s), 2.15-2.23 (2Η, m), 2.28 (2Η, t, 6 , 9 Hz), 3.28 (2Η, t, J = 5.6 Hz), 3.49-3.54 (2Η, m), 4.14 (2Η, t, J = 6.5 Hz), 6.92 (1H, d, J = 9.6 Hz), 7.01 (2Η, dd, J = 8.7 Hz, 8.7 Hz), 7.12 (1Η, d, J = 9.6 Hz), 7.25-7.35 (4H, m), 7.39 (2H, dd, J = 5.5, 8.8 Hz)

Example 8

To a solution of 3- [2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -6,7-dihydropyrazol [1,5 -A] pyrimidin-4 (5H) -yl] propanoate-tertiary butyl (145 mg) in chloroform (6 mL) was added trifluoroacetic acid (6 mL), and the mixture was stirred at room temperature for 2 h. Water (10 mL) was added to the mixture, and the mixture was neutralized with NaHCO 3. The organic layer was separated and concentrated under reduced pressure to give 3- [2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] acid -6,7-dihydropyrazolo [1,5-a] pyrimidin-4 (5H) -yl] propanoic acid (110 mg) as yellow amorphous solid.

1H-NMR (500 MHz, CDCl3) δ 2.13 (3H, s), 2.16-2.19 (2H, m), 2.36 (2H, t, 7.5 Hz), 3.26 ( 2H, t, J = 5.5 Hz), 3.56 (2H, brs), 4.14 (2H, t, J = 5.8 Hz), 6.96 (1H, d, J = 9.6 Hz), 7.01 (2H, dd, J = 8.7 Hz, 8.7 Hz), 7.11 (1H, d, J = 9.6 Hz), 7.26-7.33 (4H, m), 7.37 (2H, dd, J = 5.5, 8.7 Hz)

Example 9

A mixture of 3- {6- (4-fluorophenyl) -7- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] was stirred for 50 minutes at 60 ° C. Ethyl -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-1-yl} propanoate (450 mg) and 10% aqueous NaOH solution (4 mL) in ethanol (10 mL). The solvent was removed under reduced pressure. Water (10 mL) was added to the residue. The mixture was neutralized with citric acid and extracted with EtOAc (30 mL). The extract was dried over anhydrous MgSO4 and concentrated under reduced pressure to give 3- {6- (4-fluorophenyl) -7- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3- acid pyridazinyl] -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-1-yl} propanoic acid (380 mg) as a light yellow powder.

1H-NMR (500 MHz, CDCl3) δ 2.18 (3H, s), 2.38 (2H, t, J = 6.9 Hz), 3.55 (2Η, brs), 3.85 (2Η, t, J = 8.3 Hz), 4.20 (2Η, t, J = 7.9 Hz), 6.91 (1Η, d, J = 9.7 Hz), 6.98 (1Η, d, J = 9.7 Hz), 7.07 (2H, dd, J = 8.6 Hz, 8.6 Hz), 7.27-7.33 (4H, m), 7.42 (2H, dd, J = 5.0, 8.1 Hz)

Example 10

To a solution of 3- {6- (4-fluorophenyl) -7- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -2,3-dihydro-1 H- imidazo [1,2-b] pyrazol-1-yl} propanoic acid (0.87 g) in THF (15 mL) was added NaBH4 (0.22 g) followed by BF3 / Et20 complex (0.72 mL) ) at room temperature. The mixture was stirred at room temperature for 5.5 h. To the mixture were added dichloromethane (50 mL) and saturated aqueous NaHCO 3 solution (30 mL). The mixture was stirred overnight at room temperature. The organic layer was separated and concentrated under reduced pressure. The residue was purified by flash column chromatography (elution gradient: methanol / chloroform = 5% to 10%) to give 6- [6- (4-fluorophenyl) -1- (3-hydroxypropyl) -2,3-dihydro. -1H-imidazo [1,2-b] pyrazol-7-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone as a yellow amorphous solid (0.22 g).

Mass ESI (+) 446 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 1.34 (1H, brs), 1.61-1.67 (2H, m), 2.21 (3H, s), 3.34-3.40 (4H , m), 3.83 (2H, t, J = 8.7 Hz), 4.21 (2H, t, J = 8.2 Hz), 6.85 (1H, d, J = 9.8 Hz) ), 6.95 (1H, d, J = 9.8 Hz), 7.08 (2H, dd, J = 8.2, 8.2 Hz), 7.33-7.38 (4H, m) 7.44 (2H, dd, J = 5.5, 8.4 Hz)

Example 11

To a suspension of 3- {6- (4-fluorophenyl) -7- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -2,3-dihydro 1H-imidazo [1,2-b] pyrazol-1-yl} propanoic acid (96 mg) in dichloromethane (5 mL) was added catalytic amount of DMF. To the mixture was added dropwise oxalyl chloride (23 µL) at room temperature. The mixture was stirred at room temperature for 1.5 h. The solvent was removed under reduced pressure. The residue was dissolved in chloroform (5 mL).

To a solution of morpholine (55 µL) in chloroform (5 mL) was slowly added the acid chloride solution in chloroform. The mixture was stirred for 40 minutes. Water (5 mL) was added to the mixture. The organic layer was separated and concentrated under reduced pressure.

The residue was purified by flash column chromatography (methanol / chloroform = 8%) to give 6- {6- (4-fluorophenyl) -1- [3- (4-morpholinyl) -3-oxopropyl] -2,3 -dihydro-1'-imidazo [1,2-b] pyrazol-7-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone as a yellow amorphous solid (35 mg). Mass ESI (+) 529 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.21-2.27 (5H, m), 2.92-2.96 (2H, m), 3.48-3.52 (6H, m), 3 , 62 (2H, t, J = 4.5 Hz), 3.96 (2H, t, J = 7.8 Hz), 4.16 (2H, t, J = 8.1 Hz), 6.84 (1H, d, J = 9.6 Hz), 6.93 (1H, d, J = 9.5 Hz), 7.09 (2H, dd, J = 8.1, 8.1 Hz), 7 , 30-7.38 (4H, m), 7.43 (2H, dd, J = 5.5, 8.4 Hz)

Example 12

To a mixture of 6- [6- (4-fluorophenyl) -1- (3-hydroxypropyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- (2 Methylphenyl) -3 (2H) -pyridazinone (178 mg) in triethylamine (78 μΐΟ in dichloromethane (10 mL) was added methanesulfonyl chloride (37 μL) .The mixture was stirred for 1.5 h. Dichloromethane (10 mL) was added to the mixture and washed successively with water (10 mL) and 5% aqueous NaHCO 3 solution (10 mL) The mixture was dried over anhydrous MgSO 4 and concentrated under reduced pressure. purified by flash column chromatography (elution gradient:

methanol / chloroform = 0% to 10%) to give 30 3- [6- (4-fluorophenyl) -7- (1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl) methanesulfonate ] -2,3-dihydro-1'-imidazo [1,2-b] pyrazol-1-yl] propyl as a light yellow amorphous solid (107 mg).

1H-NMR (500 MHz, CDCl3) δ 1.80-1.86 (2H, m), 2.21 (3H, s), 3.37 (2H, t, J = 6.7 Hz), 3, 82 (2H, t, J = 6.3 Hz), 3.85 (2H, t, J = 8.4 Hz), 4.23 (2H, t, J = 8.2 Hz), 6.85 ( 1H, d, J = 9.6 Hz), 6.93 (1H, d, J = 9.8 Hz), 7.10 (2H, dd, J = 8.6, 8.6 Hz), 7, 30-7.39 (4Η, m), 7.44 (2Η, dd, J = 5.4, 8.76 Hz)

Example 13

A mixture of 3- [6- (4-fluorophenyl) -7- (1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -methanesulfonate was refluxed for 2 h. 2,3-dihydro-β-imidazo [1,2-b] pyrazol-1-yl] propyl (52 mg), morpholine (10 μΐι) and anhydrous K 2 CO 3 (17 mg) in CH 3 CN (4 mL). in the mixture morpholine (15 μΙ;) and KI (10 mg), and the mixture was refluxed for 2 h.Water (20 mL) was added to the mixture.The mixture was extracted with EtOAc (30 mL). The extract was concentrated under reduced pressure.The residue was purified by flash column chromatography (elution gradient: methanol / chloroform = 5% to 10%) to give 6- {6- (4-fluorophenyl) -1 - [3]. - (4-morpholinyl) propyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone (52 mg) as a light yellow amorphous solid.

Mass ESI (+) 515 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 1.56-1.63 (2H, m), 2.01 (2H, t, J = 6.8 Hz), 2.21 (3H, s), 2, 25 (4H, brs), 3.27 (2H, brs), 3.66 (4H, brs), 3.81 (2H, t, J; = 8.3 Hz), 4.20 (2H, t, J = 7.9 Hz), 6.84 (1H, d, J = 9.6 Hz), 6.94 (1H, d, J = 9.6 Hz), 7.08 (2H, dd, J = 8.0, 8.0 Hz), 7.31-7.38 (4H, m), 7.44 (2H, dd, J = 5.4, 7.7 Hz)

Example 14

6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -3 ( 2H) -pyridazinone in a similar manner to Example 1.

1H-NMR (500 MHz, CDCl3) δ 2.28 (s, 2H), 2.30 (m, 3H), 3.22 (t, 1H, J = 11.9 Hz), 3.57 (d, 1H, J = 11.5 Hz), 3.86 (dd, 1H, J = 7.8 Hz, 12.5 Hz), 4.29 (dd, 1H, J = 4.4 Hz, 11.8 Hz ), 6.13 (brs, 1H), 6.75 (d, 1H, dd, J = 10.1 Hz), 6.89 (m, 2H), 7.27 (t, 1H, J = 14, 7 Hz), 7.52 (dd, 1H, J = 8.1 Hz, 14.6 Hz)

Example 15 A mixture of 6- [2- (2,4-difluorophenyl) -S- (dimethylamino methyl) -4,5,6,7-tetrahydropyrazol [1,5-a] was stirred at room temperature for 5 days. pyrimidin-3-yl] pyridazin-3 (2H) -one (73 mg), 2 - [(tertiary butylamino) sulfonyl] phenyl boronic acid (147 mg), cupric acetate monohydrate (8 mg) and pyridine (77 µL). ) in DMF (1.5 mL). Water (40 mL) was added to the mixture, and the mixture was extracted with EtOAc (40 mL). The extract was washed with brine (40 mL) and concentrated under reduced pressure. The residue was purified by flash column chromatography (elution gradient:

methanol / chloroform = 0% to 5%) to give N- (tertiary butyl) -2 - [3- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7 -tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -6-oxo-1 (6H) -pyridazinyl] benzene sulfonamide (74 mg) as a light brown amorphous solid. Mass ESI (+) 598 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 1.28 (9H, s), 2.22 (6H, s), 2.28-2.39 (3H, m), 3.04 (1H, brs), 3.44 (1H, d, J = 11.0 Hz), 3.77 (1H, brs), 4.24 (1H, d, J = 11.0 Hz), 5.36 (1H, s), 6.07 (1H, brs), 6.81 (1H, d, J = 10.2 Hz), 6.92 (1H, t, J = 10.0 Hz), 6.97-7.01 (2H , m), 7.50 (1H, d, J = 7.9 Hz), 7.55 (1H, dd, J = 7.8, 14.7 Hz), 7.61 (1H, t, J = 7.9 Hz), 7.70 (1H, t, J = 7.1 Hz), 8.17 (1H, d, J = 7.8 Hz)

Example 16

6- {6 - [(dimethylamino) methyl] -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2) -methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1. Mass ESI (+) 459 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 2.24 (6H, s), 2.27-2.44 (3H, m), 3.09 (1H, t, J = 9.5 Hz), 3.47 (1H, d, J = 11.8 Hz), 3.82 (1H, dd, J = 7.8 Hz, 12.4 Hz), 4.25 (1H, dd, J = 4.4 Hz, 12.2 Hz), 5.83 (1H, brs), 6.8 (1H, d, J = 9.4 Hz), 7.02 (1H, d, J = 9.9 Hz), 7.15 (2H, t, J = 8.6 Hz), 7.33-7.39 (4H, m), 7.51 (2H, dd, J = 5.5 Hz, 8.6 Hz) Example 17 There was obtained 6- {2- (2,5-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3 -yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 477 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.21 (3H, s), 2.24 (6H, s), 2.26-2.45 (3H, m), 3.09 (1H, t, J = 9.7 Hz), 3.47 (1H, d, J = 12.0 Hz), 3.82 (1H, dd, J = 8.1 Hz, 12.8 Hz), 4.27 (1H, dd, J = 5.1 Hz, 12.5 Hz), 5.90 (1H, brs), 6.38 (1H, d, J = 9.7 Hz), 7.00 (1H, dd, J = 1.4 Hz, 9.6 Hz), 7.13 (2H, t, J = 6.3 Hz), 7.29-7.36 (5H, m)

Example 18

6- [2- (4-Fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 418 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.23 (3H, s), 2.42 (1H, brs), 3.35-3.45 (2H, m), 4.17-4.23 (1H , m), 4.26 (1H, dd, J = 3.2 Hz, 13.3 Hz), 4.41 (1H, brs), 5.85 (1H, brs), 6.81 (1H, d , J = 9.9 Hz), 7.02 (1H, d, J = 9.9 Hz), 7.12-7.19 (2H, m), 7.42 (4H, m), 7.48 -7.54 (2H, m)

Example 19

6- [6- (Dimethylamino) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 445 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 2.39 (6H, s), 2.86-2.92 (1H, m), 3.27 (1H, t, J = 10.3 Hz), 3.50-3.57 (1H, m), 4.06 (1H, dd, J = 8.2, 12.4 Hz), 4.32 (1H, dd, J = 3.7, 12.6 Hz), 5.78 (1H, brs), 6.79 (1H, d, J = 9.6 Hz), 7.01 (1H, d, J = 9.6 Hz) 7.12-7.19 (2H, m), 7.30-7.42 (4H, m), 7.46-7.54 (2H, m)

Example 20

6- [2- (4-Fluorophenyl) -6- (4-morpholinyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2- methylphenyl) -3 (2Η) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 445 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 2.58-2.68 (4H, m), 2.96-3.06 (1H, m), 3.27 (1H , t, J = 9.6 Hz), 3.52-3.60 (1H, m), 3.72 (4H, t, J = 4.6 Hz), 4.04 (1H, dd, J = 9.2, 12.1 Hz), 4.34 (1H, dd, J = 4.4, 12.1 Hz), 5.78 (1H, brs), 6.80 (1H, d, J = 9 , 9 Hz), 7.02 (1H, d, J = 9.9 Hz), 7.12-7.20 (2H, m), 7.32-7.42 (4H, m), 7.47 -7.54 (2H, m)

Example 21

6- [2- (4-Fluorophenyl) -6- (isopropylamino) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 459 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 1.08 (6H, dd, J = 2.7, 6.4 Hz), 2.23 (3H, s), 2.96-3.05 (1H, m ), 3.12-3.20 (1H, m), 3.36-3.43 (1H, m), 3.43-3.50 (1H, m), 3.97 (1H, dd, J = 5.7, 12.6 Hz), 4.25 (1H, dd, J = 4.4, 12.6 Hz), 5.81 (1H, brs), 6.80 (1H, d, J = 9.9 Hz), 7.02 (1H, d, J = 9.9 Hz), 7.15 (2H, dd, J = 8.7, 8.7 Hz), 7.30-7.42 ( 4H, m), 7.47-7.54 (2H, m)

Example 22

6- {2- (4-fluorophenyl) -6 - [(methylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2) -methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 445 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 2.47-2.49 (4H, m), 2.73 (1H, dd, J = 7.7, 12.8 Hz ), 3.14-3.19 (1H, m), 3.46-3.50 (1H, m), 3.89 (1H, dd, J = 7.7, 12.8 Hz), 4, 27 (1H, dd, J = 5.0, 12.9 Hz), 5.82 (1H, brs), 6.80 (1H, d, J = 9.4 Hz), 7.01 (1H, d , J = 9.8 Hz), 7.15 (2H, dd, J = 8.8, 8.8 Hz), 7.32-7.38 (4H, m), 7.50 (2H, dd, J = 5.4, 8.7 Hz)

Example 23

6- {6 - [(dimethylamino) methyl] -2- (3-methoxyphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2) -methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 471 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 2.24 (6H, s), 2.27-2.39 (3H, m), 3.09 (1H, dd, J = 9.0, 9.0 Hz), 3.46 (1H, d, J = 11.4 Hz), 3.81 (1H, dd, J = 7.3, 12.4 Hz), 3.84 (3H, s), 3.81 (1H, dd, J = 7.3, 12.4 Hz), 3.84 (3H, s), 4.26 (1H, dd, J = 4.5, 12 , 3 Hz), 5.84 (1H, brs), 6.78 (1H, d, J = 10.2 Hz), 6.96-6.98 (1H, m), 7.08-7.10 (3H, m), 7.33-7.37 (5H, m)

Example 24

6- {2- (2,4-difluorophenyl) -6 - [(methylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 463 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.20 (3H, s), 2.49 (3H, s), 2.50-2.53 (1H, m), 2.74-2.79 (2H , m), 3.16-3.21 (1H, m), 3.48 (1H, d, J = 11.5 Hz), 3.92 (1H, dd, J = 7.4, 12.4 Hz), 4.29 (1H, dd, J = 5.0, 12.4 Hz), 5.90 (1H, brs), 6.84 (1H, d, J = 10.0 Hz), 6, 92-7.03 (4H, m), 7.32-7.39 (4H, m), 7.53 (1H, dd, J = 8.7, 15.0 Hz)

Example 25

6- {6 - [(dimethylamino) methyl] -2- (3,5-dimethylphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 469 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.23 (9H, s), 2.26-2.29 (1H, m), 2.35 (6H, s), 2.37-2.43 (2H, m), 3.08 (1H, dd, J = 9.2, 9.2 Hz), 3.46 (1H, d, J = 11.9 Hz), 3.80 (1H, dd, J = 7.8, 12.4 Hz), 4.25 (1H, dd, J = 5.0, 12.8 Hz), 5.83 ( 1H, brs), 6.77 (1H, d, J = 9.7 Hz), 7.05 (1H, s), 7.10-7.13 (3H, m), 7.34-7.38 (4H, m)

Example 26

6- {2- (2-Chloro-4-fluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -benzamide 2- (2-methylphenyl) -3 (2H) -pyridazinone similar to that of Example 1.

Mass ESI (+) 493 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.20 (3H, s), 2.25 (6H, s), 2.28-2.47 (3H, m), 3.10 (1H, t, J = 9.6 Hz), 3.47-3.51 (1H m, 3.81 (1H, dd, J = 8.7, 11.8 Hz), 4.26 (1H, dd, J = 4.6, 12.3 Hz), 5.95 (1H, brs), 6.79 (2H, d, J = I.4 Hz), 7.12 (1H, dt, J = 2.8, 8.3 Hz), 7.26-7.28 (1H, m), 7.33-7.38 (4H, m), 7.50 (1H, dd, J = 6.4, 8.6 Hz)

Example 27

6 - {6 - [(dimethylamino) methyl] -2- (3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2) -methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 1.

Mass ESI (+) 455 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 2.22 (3H, s), 2.23 (6H, s), 2.25-2.39 (3H, m), 2.40 (3H, s), 3.08 (1H, dd, J = 9.6, 9.6 Hz), 3.46 (1H, d, J = II.5 Hz), 3.80 (1H, dd, J = 7.7, 12.4 20 Hz), 4.25 (1H, dd, J = 4.6, 12.3 Hz), 5.83 (1H , brs), 6.77 (1H, d, J = 9.5 Hz), 7.08 (1H, d, J = 9.6 Hz), 7.23-7.37 (8H, m)

Example 28

6- [2- (4-Fluorophenyl) -6- (4-25-morpholinyl methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -hydrochloride was obtained. 2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 5.

Mass ESI (+) 501 (M + 1)

1H-NMR (500 MHz, DMSO-d6) δ 2.09 (3H, s), 2.72-2.82 (1H, 30 m), 3.00-3.26 (5H, m), 3.38-4.06 (8H, m), 4.29-4.38 (1H, m), 6.11 (1H, brs), 6.95 (1H, d, J = 9.5 Hz), 7.10 (1H, d, J = 9.5 Hz), 7.25 (2H, dd, J = 8.5, 18.5 Hz), 7.30-7.41 (4H, m), 7.49 (2H, dd, J = 5.5, 8.5 Hz), 10.7 (1H, brs)

Example 29

6- [2- (4-Fluorophenyl) -6 - {[(2-hydroxyethyl) (methyl) amino] methyl} -4,5,6,7-tetrahydropyrazole [1,5-a] hydrochloride was obtained. pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2Η) -pyridazinone in a similar manner to Example 5. Mass ESI (+) 489 (M + 1)

1H-NMR (500 MHz, DMS0-d6) δ 2.09 (3H, s), 2.67-2.76 (1H, m), 2.86 (3H, d, J = 4.1 Hz), 3.09-3.21 (3H, m), 3.25 -3.36 (2H, m), 3.42-3.54 (1H, m), 3.75-3.82 (2H, m), 3.92-4.00 (1H, m), 4.28-4.40 (1H, m), 6.13 (1H, brs) , 6.95 (1H, d, J = 19.5 Hz), 7.10 (1H, dd, J = 2.6, 9.5 Hz), 7.25 (2H, dd, J = 8.7, 8.7 Hz), 7.32-7.42 (4H, m ), 7.49 (2H, dd, J = 5.9, 8.7 Hz), 10.0 (1H, brs)

Example 30

6- [4-Ethyl-2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 6. Mass ESI (+) 489 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 0.96 (3H, t, J = 6.7 Hz), 2.15 (3H, s), 2.17-2.20 (2H, m), 3.21-3.25 (4H, m), 4.14 (2H, t, J = 5.9 Hz), 6.92 (1H, d, J = 9.6 Hz), 7.01 (2H, t, J = 8.6 Hz), 7.14 (1H, d, J = 9.6 Hz) , 7.20 (1H, d, J = 7.4 Hz), 7.29-7.36 (3H, m), 7.41 (2H, dd, J = 5.5, 8.7 Hz)

Example 31

3- {6- (4-Fluorophenyl) -7- [1- (2-methylphenyl) -6-oxo-1,6-dihydro-3-pyridazinyl] -2,3-dihydro-1H-imidazo [ Ethyl 1,2-b] pyrazol-1-yl} propanoate in a similar manner to Example 6. Mass ESI (+) 488 (M + 1)

1H-NMR (500 MHz, CDCl3) δ 1.21 (3H, t, J = 7.3 Hz), 2.20 (3H, s), 2.34 (2H, t, J = 6.9 Hz), 3.56 (2H, t, J = 6.4 Hz), 3.86 (2H, t, J = 8.7 Hz), 4.07 (2H, q, J = 6.9 Hz), 4.19 (2H, t, J = 7.9 Hz), 6.86 (1H, d, J = 9.6 Hz), 6.96 (1H, d, J = 9.6 Hz), 7.08 (2H, t, J = 8.7 Hz), 7.29-7.36 (4H, m), 7.43 (2H, dd, J = 5.5, 8.6 Hz)

Example 32

6- [2- (4-Fluorophenyl) -4- (3-hydroxypropyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2- methylphenyl) -3 (2H) -pyridazinone in a similar manner to Example 10.ESI mass (+) 460 (M + 1)

1H-NMR (CDCl3) δ 1.59-1.64 (2H, m), 2.15-2.19 (5H, m), 3.25 (2H, t, J = 5.5 Hz), 3.33 (2H, brs), 3.40-3.46 (3H, m) 4.14 (2H, t, J = 6.3 Hz), 6.91 (1H, d, J = 9.7 Hz), 7.01 (2H, dd, J = 8.7, 8.7 Hz), 7.12 (1HH d, J = 9.7 Hz) ), 7.23-7.36 (4H, m), 7.40 (2H, dd, J = 5.5, 8.7 Hz).

Example 33

6- {6 - [(diethylamino) methyl] -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-10-3-yl} -2 - (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (+) 506 (M + 1)

1H-NMR (CDCl3) δ 0.98 (6H, t, J = 7.4 Hz), 2.21 (3H, s), 2.37-2.43 (3H, m), 4.50 (4H, q, J = 7.34 Hz), 3.07 (1H , dd, J = 9.2, 9.2 Hz), 3.47 (1H, d, J = II.5 Hz), 3.82 (1H, dd, J = 9.2, 9.2 Hz), 4.26 (1H, dd, J = 4.1, 12.4 Hz), 5.89 (1H, brs), 6.83 (1H, d, J = 9.5 Hz), 6.92-6.97 (m, 2H), 7.01 (1H, ddd, J = 2.5, 8.3, 8.3 Hz), 7.34 -7.39 (4H, m), 7.54 (1H, dd, J = 8.3, 15.2 Hz)

Example 34

6- [6- {[Benzyl (methyl) amino] methyl} -2- (3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -benzamide 2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (+) 531 (M + 1)

1H-NMR (CDCl3) δ 2.23 (3H, s), 2.24 (3H, s), 2.38-2.42 (5H, m), 2.47-2.51 (1H, m), 3.01 (1H, dd, J = 9.7, 9.7 Hz), 3.46-3.55 (3H, m), 3.76 (1H, dd, J = 9.6, 13.3 Hz), 4.31 (1H, dd, J = 3.7, 13.3 Hz), 5.79 (1H, brs), 6.77 (1H, d, J = 9.9 Hz), 7.08 (1H, d, J = 10.0 Hz), 7.23-7.38 (13H, m)

Example 35

6- [2- (4-Fluorophenyl) -6,6-bis (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2 -methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (+) 462 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.28 (2H, s), 3.77 (4H, m), 3.99 (2Η, s), 5.80 (1Η, brs), 6.80 (1Η, d, J = 10.1 Hz), 7.02 (1Η, d, J = 10.1 Hz), 7.15 (2Η, dd, J = 8.7 Hz, J = 8.7 Hz), 7.31-7.41 (4H, m), 7.48 ( 2H, dd, J = 8.7 Hz, J = 5.5 Hz)

Example 3 6

6- {6 - [(dibenzylamino) methyl] -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-Methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (+) 629 (M + 1)

1H-NMR (CDCl3) δ 2.20 (3H, s), 2.46 (2H, d, J = 7.7 Hz), 2.51-2.57 (1H, m), 2.83-2.89 (1H, m), 3.41-3.45 ( 1H, m), 3.49 (2H, d, J = 13.8 Hz), 3.61-3.68 (3H, m), 4.36 (1H, dd, J = 5.2, 12.4 Hz), 5.78 (1H, brs), 6.82 (1H , d, J = 10.1 Hz), 6.92-6.96 (2H, m), 7.00-7.04 (1H, m), 7.21-7.39 (14H, m), 7.51-7.55 (1H, m)

Example 37

6- [2- (2,4-Difluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2- methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (+) 450 (M + 1)

1H-NMR (CDCl3) δ 2.21 (3H, s), 2.44-2.49 (1H, m), 3.24 (1H, dd, J = 9.6, 9.6 Hz), 3.46 (1H, d, J = 12.2 Hz) , 3.70-3.76 (2H, m), 3.98 (1H, dd, J = 7.5, 12.9 Hz), 4.26 (1H, dd, J = 4.9, 12.4 Hz), 5.88 (1H, brs), 6.83 (1H, d , J = 10.0 Hz), 6.92-6.97 (2H, m), 7.02 (1H, ddd, J = 1.9, 8.7, 8.7 Hz), 7.29-7.36 (4H, m), 7.54 (1H, dd, J = 8.7, 14.9 Hz)

Example 38

6- [6- (Hydroxymethyl) -2- (3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1. Mass ESI (+) 428 (M + 1)

1H-NMR (CDCl3) δ 2.23 (3H, s), 2.40 (3H, s), 2.42-2.46 (1H, m), 3.22 (1H, dd, J = 9.7, 9.7 Hz), 3.45 (1H, d, J = 11.1 Hz), 3.67-3.75 (2H, m), 3.97 (1H, dd, J = 7.4, 12.3 Hz), 4.24 (1Η, dd, J = 4.6, 12.2 Hz), 5.81 (1H, brs ), 6.77 (1H, d, J = 10.1 Hz), 7.08 (1H, d, J = 9.8 Hz), 7.22-7.37 (8H, m)

Example 39

6- [6- {[Benzyl (tertiary butyl) amino] methyl} -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1. Mass ESI (+) 595 (M + 1) 1H-NMR (CDCl3) δ 1.92 ( 9H, s), 2.20 (3H, s), 2.54-2.58 (1H, m), 2.64-2.69 (1H, m), 2.85-2.90 (1H, m), 3.25-3.29 (1H, m), 3.66 ( 1H, d, J = 15.7 Hz), 3.78-3.82 (2H, m), 4.05 (1H, dd, J = 4.6, 12.4 Hz), 5.72 (1H, brs), 6.81 (1H, d, J = 9.8 Hz) ), 6.90-6.95 (2H, m), 7.00 (1H, ddd, J = 2.3, 8.4, 15 8.4 Hz), 7.17 (1H, dd, J = 7.3, 7.3 Hz), 7.23-7.27 (2H, m) , 7.30-7.39 (6H, m), 7.51 (1H, dd, J = 8.2, 14.5 Hz)

Example 40

6- [2- (2-Chloro-4-fluorophenyl) -6,6-bis (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -benzamide 2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (-) 494 (M-I)

1H-NMR (CDCl3) δ 2.20 (3H, s), 2.27 (2H, m), 3.30 (2H, s), 3.77 (4H, m), 4.01 (2H, s), 5.92 (1H, brs), 6.78 (1H, d, 10.1 Hz), 6.81 (1H, d, J = 10.1 Hz), 7.12 (1H, ddd, J = 2.8 Hz, J = 8.2 Hz, J = 8.2 Hz), 7.26 (1H , dd, J = 2.8 Hz, J = 8.2 Hz), 7.31-7.41 (4H, m), 7.49 (1H, dd, J = 8.2 Hz, J = 6.0 Hz)

Example 41

6 - [2- (2,4-Difluorophenyl) -6,6-bis (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1. Mass ESI (-) 478 (MI) 1H-NMR (CDCl3) δ 2.21 (3H, s), 2.22 (2H, t, J = 4.6 Hz), 3.28 (2H, s), 3.76 (4H, d, J = 4.6 Hz), 4.01 (2H, s), 5.87 (1H, brs), 6.83 (1H , d, J = 9.6 Hz), 6.94 (1H, ddd, J = 2.7 Hz, J = 9.6 Hz, J = 9.6 Hz), 6.96 (1H, dd, J = 1.8 Hz, J = Q.1 Hz ), 7.01 (1H, ddd, J = 2.3 Hz, J = 6.4 Hz, J = 8.7 Hz), 7.31-7.42 (4H, m), 7.54 (1H, dt, J = 6.4 Hzi J = 8.7 Hz)

Example 42

6- [6,6-Bis (hydroxymethyl) -2- (3-methylphenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2) -methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1.

Mass ESI (+) 458 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 2.39 (3H, s), 3.22 (2H, s), 3.69 (4H, s), 3.98 (2H, s), 5.80 (1H, brs), 6.77 (1H, d, J = 9.7 Hz), 7.06 (1H, d, J = 9.6 Hz), 7.22-7.26 (2H, m), 7.30-7.39 (6H, m)

Example 43

{2- (3-Methylphenyl) -3 - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol diacetate [ 1,5-a] pyrimidine-6,6-diyl} bis (methylene) in a similar manner to Example 1. 1H-NMR (CDCl3) δ 2.06 (6H, s), 2.22 (3H, s), 2.40 (3H, s), 3.29 (2H, s), 4.07 (2H, s), 4.14 (4H, dd, J = II.5, 22.8 Hz), 5.84 (1H, brs), 6.77 (1H, d, J = 10.3 Hz), 7.08 (1H, d, J = 10.2 Hz), 7.23-7.29 (2H, m), 7.31-7.37 (6H, m)

Example 44

{6- (Hydroxymethyl) -2- (3-methylphenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5 acetate was obtained. 6,7-Tetrahydropyrazol [1,5-a] pyrimidin-6-yl} methyl according to a similar manner to Example 1.

1H-NMR (CDCl3) δ 2.11 (3H, s), 2.23 (3H, s), 2.40 (3H, s), 3.27 (2H, s), 3.57 (2H, s), 4.01 (2H, dd, J = 13.2, 37.0 Hz), 4.21 (2H, dd, J = 11.6, 45.5 Hz), 5.82 (1H, brs), 6.78 (1H, d, J = 9.6 Hz), 7.08 (1H, d, J = 9.5 Hz), 7.23-7.28 (2H, m), 7.32-7.40 (6H, m)

Example 45

6 - [(6Z) -2- (2,4-difluorophenyl) -6- (2-hydroxyethylidene) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 1. Mass (+) ESI 462 (M + 1)

1H-NMR (CDCl3) δ 2.20 (3H, s), 3.87 (2H, s), 4.27 (2H, d, J = 6.4 Hz), 4.85 (2H, s), 5.86 (1H, t, J = 6.4 Hz), 5.95 (1H, brs), 6.83 (1HH d, J = 10.1 Hz), 6.93-7.04 (3H, m), 7.32-7.38 (4H, m), 7.53 (1H, dd, J = 8.2, 15.1 Hz) Example 4 6

6- {2- (4-fluorophenyl) -6 - [(3-hydroxy azetidin-1-yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-one yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 5.

Mass ESI (+) 487 (M + 1)

1H NMR (CDCl3) δ 1.98 (1H, brs), 2.22 (3H, s), 2.24 (1H, s), 2.48-2.62 (2H, m), 2.86-2.99 (2H, m), 3.05-3. 1H, 15 m), 3.40-3.47 (1H, m), 3.63-3.74 (2H, m), 3.83 (1H, dd, J = 8.2 Hz, J = 12.6 Hz), 4.21 (1H, dd, J = 12.6 Hz, J = 5.0 Hz), 4.39-4.47 (1H, m), 5.80 (1H, brs), 6.79 (1H, d, J = 10.1 Hz), 7.01 (1H, d, J = 10.1 Hz), 7.14 ( 2H, dd, J = 8.7 Hz, J = 8.7 Hz), 7.31-7.41 (4H, m), 7.49 (2H, dd, J = 8.7 Hz, 20 J = 5.5 Hz) Example 47

6- {2- (4-Fluorophenyl) -6 - [(4-methyl-piperazin-1-yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] dihydrochloride was obtained. pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 5.

Mass ESI (+) 514 (M + 1)

1H-NMR (DMSO-d6) δ 2.09 (3H, s), 2.59-2.88 (4H, m), 3.04-4.07 (14H, m), 4.22-4.39 (1H, m), 6.95 (1H, d, J = 10.3 Hz), 7.10 (1H, d, J = 10.3 Hz), 7.21-7.39 (4H, m), 7.45-30 7.52 (2H, m)

Example 48

6- [2- (4-Fluorophenyl) -6- (pyrrolidin-1-ylmethyl) -4,5,6,7-tetrahydropyrazolo [1,5-

a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one according to a similar manner to Example 5.

Mass ESI (+) 485 (M + 1) 1H-NMR (DMSO-d6) δ 1.83-2.05 (4H, m), 2.09 (3H, s), 2.59-2.69 (1Η, m), 2.95-3.08 ( 2Η, m), 3.12-3.27 (3Η, m), 3.46-3.52 (1H, m), 3.57-3.66 (2Η, m), 3.94-4.00 (1Η, m), 4.29-4.36 (1Η, m), 6.12 (1Η, brs), 6.95 (1Η, d, J = 9.8 Hz), 7.10 (1H, d, J = 9.8 Hz), 7.21-7.29 (2Η, m), 7.30-7.40 (4Η, m) , 7.46-7.52 (2Η, m), 10.48 (1Η, brs)

Example 4 9

6- [2- (4-Fluorophenyl) -6 - {[(2-methoxyethyl) amino] methyl} -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 5.

Mass ESI (+) 489 (M + H)

1H-NMR (CDCl3) δ 2.22 (3H, s), 2.35-2.43 (1H, m), 2.70-2.72 (2H, m), 2.75-2.80 (2H, m), 3.08-3.19 (1H, m), 3.35 (3H, s), 3.42-3.51 (3H, m), 3.83-3.90 (1H, m), 4.21-4.30 (1H, m), 5.81 (1H, s), 6.79 (1H, d, J = 9.5 Hz), 7.01 (1H, d, J = 10.0 Hz), 7.10-7.18 (2H, m), 7.30-7.40 (4H, m), 7.48-7.52 (2H, m)

Example 50

2- (2-Methylphenyl) -6- (2-phenyl pyrazol [1,5-a] pyrazin-3-yl) pyridazin-3 (2H) -one was obtained in a similar manner to Example 15.

Mass ESI (+) 380 (M + 1)

1H-NMR (DMS0-d6) δ 2.16 (3H, s), 7.10 (1H, d, J = 9.9 Hz), 7.34-7.43 (4H, m), 7.44-7.48 (1H, m), 7.51-7.57 ( 3H, m) 25 7.67-7.72 (2H, m), 8.07 (1H, d, J = 4.9 Hz), 8.92 (1H, dd, J = I.4, 4.9 Hz), 9.23 (1H, d, J = I.4 Hz)

Examples 51 and 52

A racemate, 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one was separated into each of the optical isomers, (+) -6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4, 5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one and (-) - 6- {2 - (2,4 -difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) - using the chiral HPLC method. (Example 51) (+) - 6- {2- (2,4-difluorophenyl) -6-

[(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazole [1,5-a]

pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one [a] 26d = + 313 ° (c = 1.0, CHCl3)

(Example 52) (-) - 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-one yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one [a] 26d = -314 ° (c = 1.0, CHCl3) Examples 53 and 54

(+) - 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one and (-) - 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazole [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one according to a similar manner to Examples 51 and 52.

(Example 53) (+) -6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2 -

methylphenyl) pyridazin-3 (2H) -one 20 [a] 26d = + 51.3 ° (c = 0.45, CHCl3)

(Example 54) (-) - 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-

methylphenyl) pyridazin-3 (2H) -one [a] 26d = -50. 3o (c = 0.98, CHCl3) The following optical isomers can also be obtained similarly to Examples 51 and 52. (+) - 6- {2- (4-fluorophenyl) -6 - [(dimethylamino) methyl ] -4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one

(-) - 6 - {2- (4-fluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (3-methylphenyl) - 6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (3-methylphenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- ( 2-methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (2-chloro-4-fluorophenyl) -6 - [(dimethylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 2- (2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2-chloro-4-fluorophenyl) -6 - [(dimethylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 2- (2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (2,5-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-1} -2 - (2 methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2,5-difluorophenyl) -6 - [(dimethylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(+) -6- {2- (2,4-difluorophenyl) -6 - [(diethylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2,4-difluorophenyl) -6 - [(diethylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (4-fluorophenyl) -6 - [(diethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- ( 2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (4-fluorophenyl) -6 - [(diethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- ( 2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (3-methylphenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- ( 2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (3-methylphenyl) -6 - [(diethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- ( 2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (2-chloro-4-fluorophenyl) -6 - [(diethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2-chloro-4-fluorophenyl) -6 - [(diethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one (+) - 6- {2- (2,5-difluorophenyl) -6 - [(diethylamino) methyl] -

4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidin-3-yl} -2- (2-

methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2,5-difluorophenyl) -6 - [(diethylamino) methyl] -

4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidin-3-yl} -2- (2-

methylphenyl) pyridazin-3 (2H) -one

(+) - 6- [2- (2,4-difluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2 -methylphenyl) pyridazin-3 (2H) -one (-) - 6- [2- (2,4-difluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazole [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one

(+) -6- [2- (3-methylphenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-

methylphenyl) pyridazin-3 (2H) -one (-) - 6- [2- (3-methylphenyl) -6- (hydroxymethyl) -4,5,6,7-

tetrahydropyrazol [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one

(+) -6- [2- (2,5-difluorophenyl) -6- (hydroxymethyl) -4,5,6,7-20 tetrahydropyrazol [1,5-a] pyrimidin-3-yl] -2- ( 2-

methylphenyl) pyridazin-3 (2H) -one

(-) - 6- [2- (2,5-difluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2 -

methylphenyl) pyridazin-3 (2H) -one (+) - 6- [2- (2-chloro-4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazole [1,5-a ] pyrimidin-3-yl] -2- (2-

methylphenyl) pyridazin-3 (2H) -one

(-) - 6- [2- (2-chloro-4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-

30 methylphenyl) pyridazin-3 (2H) -one

(+) -6- {2- (4-fluorophenyl) -6 - [(methylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- ( 2-

methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (4-fluorophenyl) -6 - [(methylamino) methyl] -4,5,6,7-35 tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-

methylphenyl) pyridazin-3 (2H) -one

(+) -6- {2- (2,4-difluorophenyl) -6 - [(methylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2 - (2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2,4-difluorophenyl) -6 - [(methylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (2,5-difluorophenyl) -6 - [(methylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2,5-difluorophenyl) - 6 - [(methylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2 - (2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (3-methylphenyl) -6 - [(methylamino) methyl] -4,5,6,7 tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl ) pyridazin-3 (2H) -one (-) - 6- {2- (3-methylphenyl) -6 - [(methylamino) methyl] -4,5,6,77 tetrahydropyrazolo [1,5-a] pyrimidin-2-one 3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (2-chloro-4-fluorophenyl) -6 - [(methylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 2- (2-methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (2-chloro-4-fluorophenyl) -6 - [(methylamino) methyl] 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 2- (2methylphenyl) pyridazin-3 (2H) -one

(+) -6- {6 - [(tertiary butylamino) methyl] -2- (4-fluorophenyl) 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl ) pyridazin-3 (2H) -one

(-) - 6- {6 - [(terciobutylamino) methyl] -2- (4-fluorophenyl) 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2methylphenyl ) pyridazin-3 (2H) -one (+) - 6- {6 - [(tertiary butylamino) methyl] -2 - (2,4-difluorophenyl) 4,5,6,7-tetrahydropyrazol [1,5- a] pyrimidin-3-yl} -2- (2methylphenyl) pyridazin-3 (2H) -one

(-) - 6 - {6 - [(terciobutylamino) methyl] -2- (2,4-difluorophenyl) 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 2- (2methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {6 - [(tertiary butylamino) methyl] -2- (2,5-difluorophenyl) 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} - 2- (2-methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {6 - [(tertiary butylamino) methyl] -2- (2,5-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2 - (2-methylphenyl) pyridazin-3 (2H) -one (+) -6- {6 - [(tertiary butylamino) methyl] -2- (3-methylphenyl) -4,5,6,7-tetrahydropyrazole [1, 5-a] pyrimidin-3-yl} -2 - (2 -

methylphenyl) pyridazin-3 (2H) -one (-) - 6- {6 - [(terciobutylamino) methyl] -2- (3-methylphenyl) -

4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one (+) - 6- {2- (4- fluorophenyl) -6 - [(4-methyl piperazin-1-yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin -3 (2H) -one (-) - 6- {2- (4-fluorophenyl) -6 - [(4-methyl piperazin-1-yl) methyl] -4,5,6,7-tetrahydropyrazol [1, 5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one (+) - 6- {2- (2,4-difluorophenyl) -6 - [(4-methyl piperazin-1-yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one 20 (- ) -6- {2- (2,4-difluorophenyl) -6 - [(4-methyl piperazin-1-

yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one

(+) - 6- {2- (2,5-difluorophenyl) -6 - [(4-methyl piperazin-1-

yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -25 2- (2-methylphenyl) pyridazin-3 (2H) -one

(-) - 6 - {2- (2,5-difluorophenyl) -6 - [(4-methyl piperazin-1-one

yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one

(+) -6- {2- (3-methylphenyl) -6 - [(4-methyl piperazin-1-

yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one

(-) - 6- {2- (3-methylphenyl) -6 - [(4-methyl piperazin-1-

yl) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one 35 (+) -2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-one

dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [1,5-a]

pyrimidin-6-carbonitrile (-) -2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7 -tetrahydropyrazol [1,5-a] pyrimidine-6-carbonitrile

(+) -2- (2,4-difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [ 1,5-a] pyrimidine-6-carbonitrile

(-) - 2- (2,4-difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [ 1,5-a] pyrimidine-6-carbonitrile (+) -2- (2,5-difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl ] -4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidine-6-carbonitrile

(-) -2- (2,5-difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [ 1,5-a] pyrimidine-6-carbonitrile

(+) -2- (3-methylphenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [1, 5-a] pyrimidine-6-carbonitrile

(-) - 2- (3-methylphenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,6-tetrahydropyrazol [1, 5-a] pyrimidine-6-carbonitrile

Example 55

For 4 hours, a suspension of 6- {2- (2,4-difluorophenyl) - 6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazol [1,5- a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one (125 mg) and zinc (17.1 mg) in acetic acid. The reaction mixture was cooled to room temperature and adjusted to pH 9 with saturated aqueous NaHCO 3 solution. The whole mixture was extracted with ethyl acetate and THF. The organic phase was washed with brine, dried over Na 2 SO 4, filtered and evaporated in vacuo. The oil thus obtained was triturated with hexane to give 6- {2- (2,4-difluorophenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-2-one. 3-yl} -2- (2-methylphenyl) -4,5-dihydropyridazin-3 (2H) -one (121 mg).

Mass ESI (+) 479 (M + 1)

1H-NMR (DMSO-d6) δ 2.14 (3H, s), 2.17 (6H, s), 2.22 (2H, m), 2.30 (1Η, m), 2.43 (4Η, m), 2.99 (1Η, m) , 3.39 (1Η, m), 3.72 (1H, m), 4.09 (1Η, m), 6.14 (1s, m), 7.16 (1H, m), 7.25 (4Η, m), 7.35 (1Η, m), 7.50 (1Η, m) Example 56

A mixture of 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4 was heated for 60 h at 60 ° C Ethyl, 5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine-6-carboxylate (282 mg), 1 M NaOH solution (1.19 mL), MeOH (5.6 mL), and THF ( 8.5 mL). After heating the mixture was cooled to room temperature and neutralized with 1 H HCl. The mixture was extracted with CHCl3 / IPA (4/1), washed with brine and dried over MgSO4 to give 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1 acid, 6-dihydropyridazin-3-yl] 4,5,6,7-15 tetrahydropyrazol [1,5-a] pyrimidine-6-carboxylic acid (266 mg).

Mass ESI (-) 444 (M-I) Example 57

At room temperature, a mixture of 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6 acid was stirred. 7-Tetrahydropyrazol [1,5-a] pyrimidine-6-carboxylic acid (80.0 mg), WSCD HCl (41.3 mg), and cyclopropylamine (12.3 mg) in CH 2 Cl 2 (1 mL). After stirring for 2h, the mixture was extracted with CHCl3 / IPA (5/1), washed with brine, and dried over MgSO4. After removal of solvent, the crude was purified by column chromatography and crystallized from CHCl 3 / IPA (5/1) to give N-cyclopropyl-2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine-6-carboxamide (75 mg). 30 ESI Mass (+) 507 (M + Na)

1H-NMR (CDCl3) δ 0.51 (2H, m), 0.80 (2H, m), 2.20 (3H, m), 2.73 (1H, m), 2.93 (1H, m), 3.54 (2H, m), 4.40 (2H, m), 6.03 (1H, m), 6.30 (1H, m), 6.8-7.58 (8H, m) Example 58

2- (4-fluorophenyl) -3 - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [1.5] -a] pyrimidine-6-carboxamide in a similar manner to Example 57. Mass ESI (+) 467 (M + Na)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.57 (2H, brs), 4.40 (2H, brs), 6.82 (1H, d), 7.01 (1H, d), 7.17 (2H, t), 7.30 -7.43 (4H, m), 7.52 (2H, m) Example 59

2- (4-fluorophenyl) -N- (2-hydroxyethyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6 7-tetrahydropyrazol [1,5-a] pyrimidine-6-carboxamide according to a similar manner to Example 57. Mass ESI (+) 511 (M + Na)

1H-NMR (CDCl3) δ 2.21 (3H, s), 2.96 (1H, quin), 3.43 (1H, quin), 3.52 (2H, d), 3.71 (3H, m), 4.35 (2H, t), 6.81 (1H, d), 7.00 (1H, d), 7.15 (2H, t), 7.34 (4H, m), 7.49 (2H, dd)

Example 60

To a mixture of 6 - [3- (4-fluorophenyl) -5 - ({[4- (hydroxymethyl) tetrahydro-2H-thiopyran-4-yl] methyl} amino) -1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (650 mg) in CH 3 CN (30 mL) was added Et 3 N (650 mg) and methane sulfonyl chloride (221 mg) at room temperature. The mixture was stirred for 6h at 100 ° C and concentrated. The residue was diluted with 10% aqueous K 2 CO 3 and extracted with CHCl 3. The organic layer was washed with brine, dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluted with hexane / AcOEt = 1/4) to give 6- [2- (4-fluorophenyl) -2 ', 3', 4,5,5 ', 6'- hexahydrospiro [pyrazol [1,5-a] pyrimidin-6,4'-thiopyran] -3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (320 mg) as a yellow amorphous solid.

Mass ESI (+) 488 (M + 1)

1H-NMR (DMS0-d6) δ 1.70 (4H, m), 2.08 (3H, s), 2.61 (4H, m), 3.11 (2H, s), 3.89 (2H, s), 6.04 (1H, s) 6.93 (1H, d, J = 10 Hz), 7.12 (1H, d, J = 10 Hz), 7.22 (2H, t, J = 9 Hz), 7.32-7.33 (2H, m), 7.35-7.37 ( 2H, m), 7.48 (2H, dd, J = 9Hz, 6Hz) Example 61

A mixture of 6- [5 - ({[1- (bromomethyl) cyclohexyl] methyl} amino) -3- (4-fluorophenyl) -1H-pyrazol-4-yl] was stirred for 19 h at room temperature. -2- (2-methylphenyl) pyridazin-3 (2H) -one (128 mg) and K 2 CO 3 (38.6 mg) in DMF (1.3 mL) and then at 400 ° C for 3 h. The reaction mixture was poured into H 2 O (20 mL), the products extracted with EtOAc (20 mL, 2 times). The extract was washed with H 2 O (20 mL, 3 times), dried over MgSO 4, filtered and evaporated. The residue was purified by column chromatography (eluting with CHCl 3). The resulting light yellow oil was crystallized from EtOAc / hexane to give 6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [cyclohexane-1,6'-pyrazol [1,5-a ] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (26.5 mg) as a light yellow powder.

Mass ESI (+) 470 (M + 1)

1H-NMR (DMSO-ds) δ 1.32-1.51 (10H, m), 2.08 (3H, s), 3.06 (2H, s), 3.84 (2H, s), 6.00-6.04 (1H, m), 6.93 ( 1H, d, J = 9.8 Hz), 7.12 (1H, d, J = 9.8 Hz), 7.18-7.25 (2H, m), 7.30-7.38 (4H, m), 7.45-7.52 (2H, m)

Example 62

6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [cyclopentane-1,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 456 (M + 1)

1H-NMR (DMSO-d6) δ 1.38-1.45 (2H, m), 1.51-1.56 (2H, m), 1.64-1.68 (4H, m), 2.09 (3H, s), 3.02 (2H, d, J = 2 Hz), 3.85 (2H, s), 6.11 (1H, brs), 6.93 (1H, d, J = 10 Hz), 7.01 (1H, d, J = 10 Hz), 7.23 (2H, td, J = 9.0, 2.0 Hz), 7.34 (4H, m), 7.49 (2H, dd, J = 9.0, 5.0 Hz)

Example 63

6- [2 '- (4-fluorophenyl) -2,3,4', 5,5 ', 6-hexahydrospiro [pyran-4,6'-pyrazolo [1,5-a] pyrimidin] -3 '-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 472 (M + 1) 1 H NMR (DMSO-Cl 6) δ 1.48 (4Η, m), 2.08 (3Η, s), 3.15 (2Η, s), 3.60 (4Η, m), 3.96 (2Η, s), 6.07 (1Η, s), 6.93 (1Η, d, J = 10 Hz), 7.12 (1H, d, J = 10 Hz), 7.22 (2Η, t, J = 9 Hz), 7.32 -7.37 (4Η, m), 7.48 (2Η, dd, J = 9Hz, 6Hz)

Example 64

6- [6- (4-Fluorophenyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one according to a manner similar to Example 60. Mass ESI (-) 386 (MI) 10 1 H-NMR (DMSO-d 6) δ 2.21 (3H, s), 4.28-4.61 (2H, m), 6.94 (1H, d), 7.00-7.13 (3H, m), 7.29-7.38 (4H, m), 7.40-7.49 (2H, m) Example 65

6 - [(6S) -6- (benzyloxy) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 508 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.36-3.48 (2H, m), 4.07 (2H, quint, J = 4.1 Hz), 4.21 (1H, dd, J = 4.1, 12.8 Hz), 4.26 (1H, dd, J = 4.1, 12.8 Hz), 4.64 (1H, d, J = 12.1 Hz), 4.69 (1H, d, J = 12.1 Hz), 5.79 (1H, s), 6.79 (1H, d, J = 9.9 Hz), 7.01 (1H, d, J = 9.9 Hz), 7.10-7.19 (2H, m), 7.27-7.42 (9H, m), 7.47-7.54 (2H, m) .

Example 66

6 - [(6R) -6- (benzyloxy) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 508 (M + 1) 1H-NMR (CDCl3) δ 2.22 (3H, s), 3.39-3.48 (2H, m), 4.07 (2H, quint, J = 4.0 Hz), 4.21 (1H, dd, J = 4.0, 12.8 Hz),

4.27 (1H, dd, J = 4.0, 12.8 Hz), 4.65 (1H, d, J = 12.1 Hz), 4.69 (1H, d, J = 12.1 Hz), 5.79 (1H, s), 6.79 (1H, d, J = 9.9 Hz), 7.01 (1H, d, J = 9.9 Hz), 7.12-7.18 (2H, m), 7.27-7.41 (9H, m), 7.47-7.54 (2H, m) Example 6- [(6S) -6- (benzyloxy) -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 526 (M + 1)

1H-NMR (CDCl3) δ 2.21 (3H, s), 3.39-3.49 (2H, m), 4.04-4.13 (1H, m), 4.20-4.31 (2H, m), 4.65 (1HH d, J = 13.1 Hz), 4.69 (1H, d, J = 13.1 Hz), 5.87 (1H, s), 6.82 (1H, d, J = 10.0 Hz), 6.91-6.98 (1H, m), 6.95 (1H , dd, J = 1.6, 10.0 Hz), 6.98-7.07 (1H, m), 7.28-7.42 (9H, m), 7.50-7.59 (1H, m)

Example 68

6 - [(6R) -6- (benzyloxy) -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 526 (M + 1)

1H-NMR (CDCl3) δ 2.21 (3H, s), 3.39-3.49 (2H, m), 4.04-4.11 (1H, m), 4.20-4.30 (2H, m), 4.65 (1H, d, J = 12.6 Hz), 4.69 (1H, d, J = 12.6 Hz), 5.87 (1H, s), 6.83 (1H, d, J = 9.9 Hz), 6.91-6.98 (1H, m), 6.95 (1H, dd, J = I.8, 9.9 Hz), 6.98-7.04 (1H, m), 7.27-7.40 (9H, m), 7.55 (1H, dt, J = 6.4, 8.2 Hz)

Example 69

6 - [(6S) -2- (2,4-difluorophenyl) -6- (2,2-dimethyl propoxy) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3 -yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 506 (M + 1)

1H-NMR (CDCl3) δ 0.88 (9H, s), 2.21 (3H, s), 3.20 (2H, s), 3.30-3.38 (1H, m), 3.42-3.50 (1H, m), 3.92-3.98 ( 1H, m), 4.13 (1H, dd, J = 5.5, 12.6 Hz), 4.28 (1H, dd, J = 4.1, 12.6 Hz), 5.84 (1H, s), 6.83 (1H, d, J = 9.9 Hz) ), 6.90-6.98 (1H, m), 6.96 (1H, dd, J = I.8, 9.9 Hz), 7.01 (1H, dt, J = 2.6, 8.2 Hz), 7.32-7.40 (4H, m ), 7.54 (1H, dt, J = 6.6, 8.2 Hz)

Example 70 2- (2,4-Difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [obtained] Ethyl 1,5-a] pyrimidine-6-carboxylate according to a manner similar to that of Example 60.

Mass ESI (+) 493 (M + 1)

1H-NMR (CDCl3) δ 1.27 (3H, t, J = 7.0 Hz), 2.20 (3H, s), 3.16-3.21 (1H, m), 3.48-3.52 (1H, m), 3.64-3.68 ( 1H, m), 4.22 (2H, q, J = 6.8 Hz), 4.34 (1H, dd, J = 8.1, 12.4 Hz), 4.41 (1H, dd, J = 5.3, 12.7 Hz), 5.95 (1H, brs ), 6.84 (1H, d, J = 9.7 Hz), 6.92-6.97 (m, 2H), 7.00-7.04 (1H, m), 7.32-7.40 (4H, m), 7.52-7.57 (1H, m )

Example 71

2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [1.5] ethyl-a] pyrimidine-6-carboxylate according to a manner similar to that of Example 60.

Mass ESI (+) 474 (M + 1)

1H-NMR (CDCl3) δ 1.27 (3H, t, J = 7.1 Hz), 2.22 (3H, s), 3.15-3.20 (1H, m), 3.47-3.52 (1H, m), 3.65 (1H, ddd, 3.0, 3.0, 12.1 Hz), 4.22 (2H, q, J = 7.2 Hz), 4.33 (1H, dd, J = 8.2, 12.9 Hz), 4.40 (1H, dd, J = 5.5, 12.8 Hz), 5.87 ( 1H, brs), 6.80 (1H, d, J = 10.2 Hz), 7.02 (1H, d J = 10.2 Hz), 7.15 (2H, dd, J = 8.8, 8.8 Hz), 7.32-7.40 (4H, m) 7.49-7.51 (2H, m)

Example 72

6- [2- (2,4-Difluorophenyl) -5-methyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 434 (M + 1)

1H-NMR (CDCl3) δ 1.19 (3H, d, J = 6.6 Hz), 1.87-1.95 (1H, m), 2.11-2.15 (1H, m), 2.23 (3H, s), 3.53-3.57 ( 1H, m), 4.08-4.14 (1H, m), 4.20-4.25 (1H, m), 5.92 (1H, brs), 6.84 (1H, d, J = 10.2 Hz), 6.92-6.96 (2H, m) 7.01 (1H, ddd, J = 1.9, 8.1, 8.1 Hz), 7.34-7.37 (4H, m), 7.54 (1H, ddd, 7.2, 8.4, 15.3 Hz)

Example 73 6- [6- (tertiarybutoxy methyl) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-

methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 488 (M + 1)

1H-NMR (CDCl3) δ 1.17 (9H, s), 2.23 (3H, s), 2.44 (1H, brs), 3.14-3.20 (1H, m), 3.36-3.46 (3H, m), 3.92 (1H, dd, J = 7.9, 12.0 Hz), 4.23 (1H, dd, J = 5.1, 12.5 Hz), 5.81 (1H, brs), 6.80 (1H, d, J = 9.5 Hz), 7.03 (1H, d, J = 10.0 Hz), 7.15 (2H, dd, J = 8.2, 8.2 Hz), 7.33-7.40 (4H, m), 7.51 (2H, dd, J = 5.1, 8.1 Hz) Example 74

6- [2 '- (2,4-difluorophenyl) -4', 5'-dihydrospiro [cyclopropane-1,6'-pyrazolo [1,5-a] pyrimidin] -3'-yl] -2 - (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60. Mass ESI (+) 446 (M + 1)

1H-NMR (CDCl3) δ 0.71-0.76 (4H, m), 2.22 (3H, s), 3.12 (2H, s), 3.95 (2H, s), 5.95 (1H, brs), 6.84 (1H, d, 20 J = 10.2 Hz), 6.92-7.04 (3H, m), 7.34-7.39 (4H, m), 7.55 (1H, dd, J = 8.2, 14.6 Hz)

Example 75

6- [2'- (4-fluorophenyl) -4 ', 5'-dihydrospiro [cyclopropane-1,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- (2-methylphenyl ) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 428 (M + 1)

1H-NMR (CDCl3) δ 0.71-0.76 (4H, m), 2.23 (3H, s), 3.11 (2H, d, J = 1.9 Hz), 3.94 (2H, s), 5.88 (1H, brs) 6.80 (1H, d, J = 10.1 Hz), 7.03 (1H, d, J = 10.2 Hz), 7.15 (2H, dd, J = 8.7, 8.7 Hz), 7.34-7.38 (4H, m), 7.49- 7.52 (2H, m) Example 7 6

2- (2-methylphenyl) -6- [2 '- (3-methylphenyl) -4', 5'-dihydrospiro [cyclopropane-1,6'-pyrazol [1,5-a] pyrimidin] -3 '-yl] pyridazin-3 (2H) -one in a similar manner to Example 7. Mass ESI (+) 424 (M + 1) 1H-NMR (CDCl3) δ 0.70-0.76 (4Η, m) , 2.24 (3s, s), 2.40 (3s, s), 3.11 (2s, brs), 3.94 (2s, s), 5.88 (1H7s), 6.78 (1H, d, J = 10.0 Hz), 7.10 (1s, d, J = 9.8 Hz), 7.23-7.39 (8Η, m)

Example 77

6- [2 '- (2,4-difluorophenyl) -4', 5'-dihydrospiro [cyclobutane-1,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2 - (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 7.

Mass ESI (+) 941 (2M + Na)

1H-NMR (CDCl3) δ 1.96-2.09 (6H, m), 2.22 (3H, s), 3.26 (2H, s), 4.05 (2H, s), 5.90 (1H, brs), 6.82 (1H, d, J = 9.7 Hz), 6.92-6.97 (2H, m), 7.01 (1H, ddd, 2.5, 7.8, 7.8 Hz), 7.35-7.39 (4H, m), 7.55 (1H, ddd, J = 6.4, 8.3, 8.3 Hz)

Example 78

6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [cyclobutane-1,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 7.

Mass ESI (+) 905 (2M + Na)

1H-NMR (CDCl3) δ 1.96-2.11 (6H, m), 2.23 (3H, s), 3.26 (2H, s), 4.04 (2H, s), 5.83 (1H, brs), 6.79 (1H, d, J = 10-Hz), 7.02 (1H, d, J = 9.6 Hz), 7.14 (2H, dd, J = 8.8, 8.8 Hz), 7.34-7.39 (4H, m), 7.48-7.51 (2H, m )

Example 79

In a mixture of 6- [3- (2,4-difluorophenyl) -5- ({[3- (hydroxymethyl) azetidin-3-yl] methyl} amino) -1H-pyrazol-4-yl] -2- (2 -methylphenyl) pyridazin-3 (2H) -one (73 mg) and polystyrene-supported triphenylphosphine (1 mmol / d, 280 mg) in dichloromethane (2 mL) was added diethyl azo dicarboxylate (44 mL), and stirred The mixture is stirred for 1 h at room temperature. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. To the residue was added polystyrene-supported triphenylphosphine (1 mmol / d, 210 mg), dichloromethane (2 mL) and diethyl azo dicarboxylate (33 mL), and the mixture was stirred at room temperature overnight. Insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by SiO 2 flash column chromatography (eluent: 0% methanol in chloroform 5 to 8% methanol in chloroform) to give 6- [2 '- (2,4-difluorophenyl) -1-isopropyl] 4 ', 5'-Dihydrospiro [azetidine-3,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one as an amorphous solid yellow (54 mg).

Mass ESI (+) 503 (M + 1)

1H-NMR (CDCl3) δ 0.93 (6H, d, J = 6.2 Hz), 2.21 (3H, s), 2.36-2.42 (1H, m), 3.07 (2H, d, J = 7.8 Hz), 3.23 (2H , d, J = 1.1 Hz), 3.46 (2H, s), 4.18 (2H, s), 5.96 (1H, brs), 6.83 (1H, d, J = 9.9 Hz), 6.92-6.96 (2H, m) 7.01 (1H, ddd, 15 J = 2.3, 8.3, 8.3 Hz), 7.32-7.40 (4H, m), 7.54 (1H, dd, 8.3, 14.8 Hz)

Example 80

6- [6- (2,4-Difluorophenyl) -2,2-dimethyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- (2- methylphenyl) 20 pyridazin-3 (2H) -one in a similar manner to Example 7. Mass ESI (+) 434 (M + 1) 1H-NMR (CDCl3) δ 1.51 (6H, s), 2.21 (3H, s), 4.01 (2H, s), 4.30 (1H, s), 6.86 (1H, d, J = 10.1 Hz), 6.91-6.99 (3H, 25 m), 7.33-7.39 (4H, m) 7.56 (1H, dd, J = 8.2, 14.7 Hz)

Example 81

6- [(3R) -6- (2,4-difluorophenyl) -3-methyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner 30 as in Example 7.

Mass ESI (-) 419 (M + 1)

1H-NMR (CDCl3) δ 1.60 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.60-3.64 (1H, m), 4.15 (1H, dd, J = 8.2, 8.2 Hz), 4.42 (1H, brs), 4.53-4.60 (1H, m), 6.86 (1H, d, J = 9.7 Hz), 35 6.91-6.98 (2H, m), 7.01 (1H, ddd, J = 2.7, 8.3 , 8.3 Hz), 7.31-7.38 (4H, m), 7.57 (1H, dd, J = 8.3, 15.1 Hz) Example 82 6 - [(3S) -6- (2,4-difluorophenyl) -3- methyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 7 .

Mass ESI (-) 419 (M + 1)

1H-NMR (CDCl3) δ 1.60 (3H, d, J = 6.6 Hz), 2.20 (3H, s), 3.60-3.64 (1H, m), 4.15 (1H, dd, J = 8.2, 8.2 Hz) , 4.42 (1H, brs), 4.53-4.60 (1HH m), 6.86 (1H, d, J = 9.7 Hz), 6.91-6.98 (2H, m), 7.01 (1H, ddd, J = 2.7, 8.3) , 8.3 Hz), 7.31-7.38 (4H, m), 7.57 (1H, dd, J = 8.3, 15.1 Hz)

Example 83

6 - [(7aS) -2- (2,4-difluorophenyl) -6,7,7a, 8-tetrahydro-5H-pyrrol [1 ', 2', 3,4] imidazo [1,2- b] pyrazol-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 7.

Mass ESI (+) 446 (M + 1)

1H-NMR (CDCl3) δ 1.70-1.78 (1H, m), 1.84-2.00 (2H, m), 2.14 (3H, s), 2.16-2.22 (1H, m), 3.32-3.30 (2H, m), 4.14 (1H, dd, J = 5.0, 10.7 Hz), 4.31 (1H, dd, J = 9.4, 9.4 Hz), 4.49-4.55 (1H, m), 6.81 (1H, dd, J = 9.4, 9.4 Hz) 6.90-6.94 (2H, m), 7.13 (1H, d, J = 9.5 Hz), 7.27-7.34 (4H, m), 7.49-7.53 (1H, m)

Example 84

6 - [(2R) -6- (4-fluorophenyl) -2-methyl-2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 402 (M + 1)

1H-NMR (CDCl3) δ 1.44 (3H, d, J = 6.0 Hz), 2.23 (3H, s), 3.79 (1H, dd, J = 8.0 Hz, J = 9.5 Hz), 4.37 (1H, dd, J = 8.0 Hz, J = 9.5 Hz), 4.48 (1H, brs), 4.47-4.55 (1H, m), 6.84 (1H, d, J = 10.0 Hz), 7.04 (1H, d, J = 10.0 Hz) ), 7.14 (2H, dd, J = 8.5 Hz, J = 8.5 Hz), 7.33-7.40 (4H, m), 7.51 (2H, dd, J = 5.5 Hz, J = 8.5 Hz)

Example 85

6- [6,6-Difluoro-2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 61.

Mass ESI (+) 438 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.62 (2H, t, 11.0 Hz), 4.46 (2H, t, 12.0 Hz), 5.99 (1H, brs), 6.83 (1H, d, J = 10 Hz), 7.01 (1H, d, J = 10.1 Hz), 7.16 (2H, dd, J = 8.7 Hzi J = 8.7 Hz), 7.32-7.42 (4H, m), 7.50 (2H, dd, J = 8.7 Hz, J = 5.5 Hz)

Example 86

6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [1,3-dioxolan-2,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 61.

Mass ESI (+) 460 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.33 (2H, s), 4.06-4.16 (4H, m), 4.15 (2H, s), 5.96 (1H, brs), 6.79 (1H, d, 10.1 Hz), 7.00 (1H, d, J = 10.1 Hz), 7.15 (2H, dd, J = 8.7 Hz, J = 8.7 Hz), 7.31-7.41 (4H, m), 7.50 (2H, dd, J = 5.5 Hz, J = 8.7 Hz)

Example 87

6- [(2R) -2 - [(benzyloxy) methyl] -6- (4-fluorophenyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -benzamide 2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 530 (M + Na)

1H-NMR (CD3Cl) δ 2.95 (3H, s), 3.61 (2H, d, J = 6.4 Hz), 3.69 (1H, brs), 4.01-4.06 (2H, m), 4.37 (1H, m), 4.54 (2H, s), 6.86 (1H, d), 7.03 (1H, d, J = 9.8 Hz), 7.11-7.66 (13H, m), 8.03 (1H, s)

Example 88

6- [(2S) -2 - [(benzyloxy) methyl] 6- (4-fluorophenyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -benzamide 2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 530 (M + Na) Example 89

2 '- (4-fluorophenyl) -3' - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -6 ', 7'-dihydro-1,4 Esp-spiro

Benzyl [piperidine-4,5'-pyrazol [1,5-a] pyrimidine] -1-carboxylate in a similar manner to Example 60.

Mass ESI (+) 605 (M + 1) Example 90

6- [2 '- (4-fluorophenyl) -2,3,5,6,6', 7'-hexahydro-4'H-spiro [pyran-4,5'-pyrazol [1,5- a] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60. Mass ESI (+) 472 (M + 1)

1H-NMR (CDCl3) δ 1.48-1.56 (2H, m), 1.68-1.79 (2H, m), 2.01 (2H, t, J = 6 Hz), 2.25 (3H, s), 3.07-3.22 (2H, m) 3.60-3.75 (2H, m), 4.18 (2H, t, J = 6 Hz), 6.79-6.83 (1H, 15 m), 6.83 (1H, d, J = 10 Hz), 7.06 (1H, d, J = 10 Hz), 7.14-7.19 (2H, m), 7.35-7.39 (4H, m), 7.48-7.53 (2H, m)

Example 91

6- [2- (4-Fluorophenyl) -1 ', 1'-dioxide-2', 3 ', 4,5,5', 6'-hexahydrospiro [pyrazolo [1,5-a] pyrimidine 6,4'-1opyran] -3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60. Mass ESI (+) 542 (M + Na )

1H-NMR (DMS0-d6) δ 1.86-1.98 (4H, m), 2.09 (3H, s), 3.13 (4H, m), 3.22 (2H, brs), 4.02 (2H, s), 6.11 (1H, 6.94 (1H, d, J = 10 Hz), 7.13 (1H, d, J = 10 Hz), 7.23 (2H, t, J = 9 Hz), 7.32-7.38 (4H, m), 7.49 (2H, dd, J = 9Hz, 5Hz) Example 92

2 '- (4-fluorophenyl) -3' - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4 ', 5'-dihydro-1H-spiro tertiary butyl [piperidine-4,6'-pyrazol [1,5-a] pyrimidine] -1-carboxylate in a similar manner to that of

Example 60.

Mass ESI (+) 593 (M + Na) 1 H NMR (CDCl 3) δ 1.39-1.51 (4H, m), 1.46, 1.47 (9H, s), 35 2.23, 2.93 (3H, s), 3.12-3.32 (8H, m), 5.88, 6.20 (1H, br), 6.57-7.56 (10H, m)

Example 93 6 - [(5S) -5 - ({[tertiary butyl (diphenyl) silyl] oxy} methyl) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazol [1,5- a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

1H-NMR (DMSO-d6) δ 0.90 (9H, s), 1.97-2.00 (1H, m), 2.03 (3H, s), 2.15-2.23 (1H, m), 3.52-3.68 (3H, m), 4.00-4.05 (2H, m), 6.03 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.07 (1H, d, J = 10 Hz), 7.19-7.57 (18H, m)

Example 94

6 - [(5R) -5 - ({[tertiary butyl (diphenyl) silyl] oxy} methyl) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a ] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

1H-NMR (DMSO-d6) δ 0.90 (9H, s), 1.97-2.00 (1H, m), 2.03 (3H, s), 2.15-2.23 (1H, m), 3.52-3.68 (3H, m), 4.00-4.05 (2H, m), 6.03 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.07 (1H, d, J = 10 Hz), 7.19-7.57 (18H, m)

Example 95

A mixture of 6 - [(6S) -6- (benzyloxy) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one (430 mg) and palladium hydroxide (250 mg, 20 wt% on carbon) in EtOH (20 mL) was stirred in a hydrogen atmosphere at 45-50 ° C for 6 hours. To the reaction mixture was further added palladium hydroxide (50 mg, 20 wt% on carbon) the mixture was stirred under a hydrogen atmosphere at 50 ° C for 1 hour. After separating the catalyst by filtration, the filtrate was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (elution gradient: EtOAc / hexane = 1/2 to 1 / l) followed by crystallization of a mixed solvent of diethyl ether and dichloromethane to give 6 - [(6S) - 2- (4-fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (115 mg) as light yellow crystals. Mass ESI (+) 418 (M + 1)

1H-NMR (CDCl3) δ 2.23 (3H, s), 2.37 (1H, d, J = 1.2 Hz), 3.35-3.45 (2H, m), 4.17-4.23 (1H, m), 4.26 (1H, dd, J = 3.4 Hz, 13.1 Hz), 4.38-4.46 (1H, m), 5.85 (1H, s), 6.81 (1H, 5 d, J = 9.6 Hz), 7.03 (1H, d, J = 9.6 Hz ), 7.12-7.19 (2H, m), 7.31-7.42 (4H, m), 7.48-7.54 (2H, m) Example 96

6- {6 - [(methylamino) methyl] -2- (3-methylphenyl) -

4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95. ESI Mass Spec (+) 441 (M + 1)

1H-NMR (CDCl3) δ 2.23 (3H, s), 2.37-2.40 (1H, m), 2.45 (3H, s), 2.69 (2H, d, J = 6.8 Hz), 3.14 (1H, dd, J = 9.1 Hz, J = 9.1 Hz), 3.47 (1H, d, J = 12.0 Hz), 3.86 (1H, dd, J = 8.2 Hz, 12.9 Hz), 4.27 (1H, dd, J = 5.1, 12.9 Hz), 5.83 (1H, brs), 6.77 (1H, d, J = 10.2 Hz), 7.08 (1H, d, J = 9.9 Hz), 7.23-7.39 (8H, m) Example 97

6- [6- (Aminomethyl) -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2- methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95. Mass ESI (+) 449 (M + 1) 1H-NMR (DMS0-d6) δ 2.03 (3H, s), 2.90 -2.92 (2H, m), 3.12 (1H, dd, J = 8.3, 12.4 Hz), 3.95 (1H, dd, J = 7.8, 12.9 Hz), 4.28 (1H, dd, J = 5.2, 12.5 Hz), 6.18 (1H, brs), 6.96 (1H, d, J = 10.3 Hz), 7.13-7.18 (2H, m), 7.22 (1H, d, J = 7.4 Hz), 7.28-7.37 (4H, m) 7.51-7.56 (1H, m)

Example 98

6- {6 - [(tertiary butylamino) methyl] -2- (2,4-difluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl} -2- (2-Methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95.

Mass ESI (+) 505 (M + 1)

1H-NMR (CDCl3) δ 1.14 (9H, d, J = 5.1 Hz), 2.18 (3H, s), 2.21 (2H, s), 2.52 (1H, brs), 3.27-3.53 (1H, m) , 3.52-3.57 (1Η, m), 3.91-4.02 (1Η, m), 4.29-4.34 (1Η, m), 5.86 (1Η, brs), 6.84 (1Η, d, J = 10.1 Hz), 6.90 -7.01 (4Η, m), 7.29-7.36 (3Η, m), 7.49-7.54 (1Η, m)

Example 99

6- [(6S) -2- (2,4-difluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95.

Mass ESI (+) 436 (M + 1)

1H-NMR (CDCl3) δ 2.21 (3H, s), 2.37 (1H, d, J = 6.9 Hz), 3.35-3.49 (2H, m), 4.18-4.25 (1H, m), 4.27 (1H, dd, J = 3.4, 13.1 Hz), 4.40-4.47 (1H, m), 5.92 (1H, s), 6.84 (1H, d, J = 9.7 Hz), 6.92-7.06 (2H, m), 6.97 (1H, dd, J = 2.1, 9.7 Hz), 7.30-7.42 (4H, m), 7.55 (1H, dt, J = 6.4, 8.4 Hz)

Example 100

6- [(6R) -2- (4-fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2- methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95.

Mass ESI (+) 418 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.36-3.50 (2H, m), 4.20-4.53 (3H, m), 6.00 (1H, s), 6.83 (1H, d, J = 9.6 Hz) 7.02 (1H, d, J = 9.6 Hz), 7.18 (2H, t, J = 8.2 Hz), 7.30-7.41 (4H, m), 7.50-7.58 (2H, m)

Example 101

6- [(6R) -2- (2,4-difluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95.

Mass ESI (+) 436 (M + 1)

1H-NMR (CDCl3) δ 2.21 (3H, s), 2.33 (1H, d, J = 6.9 Hz), 3.35-3.49 (2H, m), 4.18-4.25 (1H, m), 4.27 (1H, dd, J = 3.4, 13.1 Hz), 4.40-4.47 (1H, m), 5.92 (1H, s), 6.85 (1H, d, J = 10.0 Hz), 6.92-7.06 (2H, m), 6.97 (1H, dd, J = 2.1, 10.0 Hz), 7.30-7.41 (4H, m), 7.55 (1H, dt, J = 6.4, 8.2 Hz) Example 102

6- [2 '- (4-fluorophenyl) -6', 7'-dihydro-4'Η-

spiro [piperidin-4,5'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to that of Example 95. Mass ESI (+) 471 (M + 1)

1H-NMR (DMS0-d6) δ 1.38-1.82 (6H, m), 2.10 (3H, s), 2.71-2.90 (2H, m), 2.96-3.11 (2H, m), 4.01-4.17 (2H, m) ), 6.23 (1H, s), 6.97 (1H, d, J = 10.2 Hz), 7.15 (1H, d, J = 9.4 Hz), 10 7.21-7.29 (2H, m), 7.32-7.44 (4H, m ), 7.45-7.55 (2H, m)

Example 103

6- [(2R) -6- (4-fluorophenyl) -2- (hydroxymethyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2 - (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95.

ESI (+) 440 (M + Na)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.65-3.86 (2H, m), 4.05-4.19 (2H, m), 4.36 (1H, t), 4.54 (1H, m), 6.85 (1H, d), 7.03 (1H, d), 7.09-7.55 (8H, m) 20 Example 104

6- [(2S) -6- (4-fluorophenyl) -2- (hydroxymethyl) -2,3-dihydro-1H-imidazo [1,2-b] pyrazol-7-yl] -2- ( 2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 95. 25 mass ESI (+) 440 (M + Na)

Example 105

To a mixture of 2 '- (4-fluorophenyl) -3' - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4 ', 5'-dihydro-1 H- tertiary butyl spiro [piperidine-4,6'-pyrazol [1,5-a] pyrimidine] -1-carboxylate 30 (223 mg) and dioxane (2.23 mL) were added 4 M HCl / dioxane (2.23 mL), the whole mixture was stirred at room temperature for 4 h. The reaction mixture was evaporated, H 2 O (20 mL) was added to the residue, and the mixture was washed with CHCl 3 (20 mL, 2 times). The aqueous layer was neutralized with NaHCO 3 and extracted with CHCl 3 (20 mL, 2 times). The extract was dried over anhydrous MgSO4, filtered and evaporated. To the residue was added EtOAc and 4% HCl / dioxane, and then the mixture was evaporated. The residue was vacuum dried to give 6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [piperidine-4,6'-pyrazol [1,5-a]

pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (156 mg) as a light yellow foam.

Mass ESI (+) 471 (M + 1)

Example 106

To a mixture of 6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [piperidine-4,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one (150 mg) and MeCN (3 mL) were added ethyl iodide (215 mg) and K 2 CO 3 (123 mg), the whole mixture was stirred at room temperature. environment for 19 h. The reaction mixture was evaporated, and the residue was diluted with H 2 O (20 mL) and extracted with CHCl 3 (20 mL, 2 times). The extract was dried over anhydrous MgSO4, filtered and evaporated. The residue was purified by column chromatography (eluent: 5% MeOH in CHCl 3). The obtained compound (51 mg) was dissolved in dioxane (0.5 mL), treated with 4 M HCl / dioxane (0.1 mL) and concentrated to give 6- [1-ethyl-2 '- (4- fluorophenyl) -4 ', 5'-dihydrospiro [piperidin-4,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) - one (51.6 mg) as a light yellow foam. Mass ESI (+) 499 (M + 1) 1H-NMR (DMS0-d6) δ 1.20-1.28 (3H, m), 1.68-1.88 (4H, m), 2.06-2.13 (3H, m), 2.96- 3.16 (5H, m), 3.29-3.43 (3H, m), 3.83-3.86 (1H, m), 4.17-4.23 (1H, m), 6.95 (1H, d, J = 9.8 Hz), 7.11-7.17 ( 1H, m), 7.20-7.28 (2H, m), 7.30-7.39 (4H, m), 7.46-7.54 (2H, m), 10.04-10.28 (1H, m) 3

Example 107 '

To a mixture of 6- [1-acetyl-2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [piperidine-4,6'-pyrazol [1,5-a] pyrimidin] -3'-yl ] -2- (2-methylphenyl) pyridazin-3 (2H) -one (120 mg) and CH 2 Cl 2 (2 mL) were added Ac 2 O (0.034 mL) and triethylamine (0.086 mL) in an ice bath and stirred the whole mixture at room temperature for 4 h. The reaction mixture was diluted with EtOAc (30 mL), washed with H 2 O and brine (20 mL each), dried over MgSO 4 and evaporated. The residue was purified by column chromatography (eluent: 5% MeOH in CHCl 3) to give 6- [1-acetyl-2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [piperidine-4,6 ' -pyrazol [1,5-a] pyrimidin] -3'-5-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (74 mg). Mass ESI (+) 535 (M + Na)

1H-NMR (CDCl3) δ 1.56-1.68 (4H, m), 2.10 (3H, s), 2.23 (3H, s), 3.17-3.23 (2H, m), 3.46-3.59 (3H, m), 3.71- 3.79 (1H, m), 4.02-4.16 (2H, m), 5.96 (1H, br s), 6.83 (1H, d, 10 J = 9.8 Hz), 7.04 (1H, d, J = 9.8 Hz), 7.18 (2H, t, J = 8.7 Hz), 7.31-7.43 (4H, m), 7.51-7.57 (2H, m) Example 108

6- [2 '- (4-fluorophenyl) -1- (2-hydroxyethyl) -4', 5'-dihydrospiro [piperidine-4,6'-pyrazolo [1,5-a] pyrimidin] -3 '-15 yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 106. Mass ESI (+) 515 (M + 1)

1H-NMR (CDCl3) δ 1.68-1.73 (4H, m), 2.23 (3H, s), 2.53-2.67 (6H, m), 3.14-3.18 (2H, m), 3.66 (2H, t, J = 5 Hz), 3.96 (2H, s), 5.81 (1H, br), 6.80 (1H, d, J = 10 Hz), 7.03 (1H, d, J = 10 Hz), 7.12-7.18 (2H, m), 7.34-7.40 (4H, m), 7.48-7.52 (2H, m)

Example 109

6- [2 '- (4-fluorophenyl) -1- (3-hydroxypropyl) -4', 5'-dihydrospiro [piperidine-4,6'-pyrazol [1,5-a]

pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 106. Mass ESI (+) 529 (M + 1)

1H-NMR (CDCl3) δ 1.57-1.80 (6H, m), 2.22 (3H, s), 2.42-30 2.79 (6H, m), 3.14 (2H, s), 3.80 (2H, t, J = 5 Hz ), 3.95 (2H, s), 5.80 (1H, s), 6.80 (1H, d, J = 10 Hz), 7.03 (1H, d, J = 10 Hz), 7.10-7.20 (2H, m), 7.32 -7.42 (4H, m), 7.47-7.53 (2H, m)

Example 110

6- [1-Acetyl-2 '- (4-fluorophenyl) -6', 7'-dihydro-4'H-spiro [piperidine-4,5'-pyrazol [1,5-a] pyrimidin] - 3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 107. Mass ESI (+) 513 (M + 1)

1H-NMR (DMSO-d6) δ 1.44-1.70 (4H, m), 1.95-2.02 (5H, m), 2.08 (3H, s), 2.78 (1H, t), 3.52 (1H, d), 3.89 ( 1H, d), 4.08 (2H, t), 6.50 (1H, brs), 6.95 (1H, d), 7.08 (1H, d), 7.22-7.41 (6H, m), 7.46-7.58 (2H, q) Example 111

N- ({2- (2,4-difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7 tetrahydropyrazol [1,5-a] pyrimidin-6-yl} methyl) cyclopropane carboxamide in a similar manner to Example 107.

Mass ESI (+) 517 (M + 1)

1H-NMR (CDCl3) δ 0.72-0.76 (2H, m), 0.93-0.96 (2H, m), 1.29-1.34 (1H, m), 2.20 (3H, s), 2.52 (1H, brs), 3.14 ( 1H, dd, J = 8.7, 8.7 Hz), 3.27-3.32 (1H, m), 3.35-3.42 (2H, m), 3.91 (1H, dd, J = 7.2, 12.4 Hz), 4.21 (1H, dd, J = 4.7, 12.5 Hz), 5.87 (1H, brs), 6.08 (1H, brs), 6.83 (1H, d, J = 10-Hz), 6.92-6.97 (2H, m), 7.00 -7.05 (1H, m), 7.31-7.36 (4H, m), 7.53 (1H, dd, J = 8.2, 15.1 Hz)

Example 112

1- ({2- (2,4-difluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7 tetrahydropyrazol [1,5-a] pyrimidin-6-yl} methyl) -3-ethylurea in a similar manner to Example 107.

Mass ESI (+) 520 (M + 1)

1H-NMR (CDCl3) δ 1.07 (3H, t, J = 7.4 Hz), 2.19 (3H, s), 2.48 (1H, brs), 3.12-3.22 (4H, m), 3.26 (1H, brs), 3.40 (1H, d, J = 10.9 HZ), 3.90 (1H, dd, J = 6.9, 12.3 Hz), 4.19 (1H, dd, J = 5.0, 12.9 Hz), 4.54 (1H, brs), 4.86 (1H, brs), 5.86 (1H, brs), 6.82 (1H, d, J = 10 Hz), 6.92-6.97 2H, m), 7.01 (1H, ddd, J = 2.4, 7.9, 7.9 Hz), 7.30- 7.36 (4H, m), 7.52 (1H, dd, J = 8.2, 14.5 Hz)

Example 113

To a mixture of 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl ) pyridazin-3 (2H) -one (300 mg) in pyridine (1.47 g) was added acetic anhydride (277 mg) at room temperature. After stirring for 14 h, the mixture was concentrated and partitioned between EtOAc and 5% aqueous citric acid. The organic layer was washed with saturated aqueous NaHCO 3 solution and brine, dried over Na 2 SO 4, filtered and concentrated. The residue was triturated with IPE to give {2- (4-fluorophenyl) -3 - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6-acetate. , 7-Tetrahydropyrazolo [1,5-a] pyrimidin-6-yl} methyl (248 mg) as yellow powder. Mass ESI (+) 474 (M + 1)

1H-NMR (DMSO-d6) δ 2.05 (3H, s), 2.09 (3H, s), 3.04-3.14 (1H, m), 3.28-3.41 (2H, m), 3.84-3.92 (1H, m), 4.06 (2H, d, J = 7.3 Hz), 4.18 (1H, dd, J = 4.8, 11.7 Hz), 6.04 (1H, s), 6.93 (1H, d, J = 10.4 Hz), 7.09 (1H , d, J = 104 Hz), 7.19-7.26 (2H, m), 7.31-7.38 (4H, m), 7.45-7.51 (2H, m). Example 114

2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [1.5] tert-butyl pyrimidin-6-yl carbonate in a similar manner to Example 113.

1H-NMR (CDCl3) δ 1.48 (9H, s), 2.22 (3H, s), 3.45-3.61 (2H, m), 4.28-4.41 (2H, m), 5.18-5.26 (1H, m), 5.83 ( 1H, s), 6.80 (1H, d, J = 9.9 Hz), 7.01 (1H, d, J = 9.9 Hz), 7.15 (2H, t, J = 9.2 Hz), 7.30-7.43 (4H, m), 7.47-7.55 (2H, m)

Example 115

To a solution of 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl ) pyridazin-3 (2H) -one (1.08 g) in DMSO (15 mL) was added Et 3 N (2.53 g), and the solution was stirred at room temperature for 5 minutes. To the solution was added dropwise SO3 / pyridine complex (1.59 g) in DMSO (5 mL) over a period of 15 minutes, and the solution was stirred at room temperature for 5 hours. EtOAc (30 mL) was added to the solution, the solution was washed successively with 10% aqueous citric acid solution (30 mL, 4 times), saturated aqueous NaHCO 3 solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo to give 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7- tetrahydropyrazol [1,5-a] pyrimidine-6-carbaldehyde (863 mg) as a yellow solid.

Mass ESI (-) 428 (M-I)

1H NMR (CDCl3) δ 2.22 (3H, s), 3.09 (1H, m), 3.63-3.76 (2H, s), 4.31 (1H, dd, J = 5.0 Hz, J = 13.0 Hz), 4.60 ( 1H, dd, J = 5.0 Hz, J = 13.0 Hz), 5.87 (1H, brs), 6.80 (1H, d, J = 10.1 Hz), 7.00 (1H, d, J = 10.1 Hz), 7.15 (2H, dd, J = 8.7 Hz, J = 8.7 Hz), 7.31-7.41 (4H, m), 7.49 (2H, dd, J = 8.7 Hz, J = 5.5 Hz), 9.79 (1H, s) Example 116

To a solution of 2- (4-fluorophenyl) -3 - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,6-tetrahydropyrazol [1, 5-a] pyrimidine-6-carbaldehyde (215 mg) in MeOH (7 mL) was added 50% aqueous hydroxylamine solution (1.5 mL) and dichloromethane (1 mL) at room temperature. After stirring for 1 day at room temperature, the mixture was evaporated in vacuo. The crystalline residue was washed with a mixed solvent of dichloromethane and diethyl ether to give 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl oxime ] -4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidine-6-carbaldehyde (150 mg) as a light yellow solid.

Mass ESI (+) 445 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.08-3.17 (1H, m), 3.23-3.31 (1H, m), 3.53-3.62 (1H, m), 4.24 (2H, dd, J = 8.9 , 13.1 Hz), 4.49 (2H, dd, J = 4.8, 13.1 Hz), 5.91 (1H, s), 6.81 (1H, d, J = 10.1 Hz), 7.02 (1H, d, J = 10-Hz), 7.13-7.19 (2H, m), 7.31-7.41 (4H, m), 7.46-7.53 (3H, m), 8.95 (1H, s) Example 117

A solution of 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazol [1] oxime solution 5-a] pyrimidine-6-carbaldehyde (45 mg) in formic acid (1 mL) was stirred at reflux for 1 day. Water (20 mL) was added to the reaction mixture and the mixture was extracted with dichloromethane. The organic layer was washed successively with 5% aqueous Na 2 CO 3 solution and brine, dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (elution gradient: MeOH / chloroform = 0/1 to 1/19) followed by crystallization of a mixed solvent of diethyl ether and dichloromethane to give 2- (4-fluorophenyl ) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine-6-carbonitrile ( 20 mg) as a light yellow solid.

Mass ESI (+) 427 (M + 1)

1H-NMR (CDCl3) δ 2.22 (3H, s), 3.39 (1H, quint, J = 5.2 Hz), 4.59-4.67 (2H, m), 4.41 (2H, d, J = 5.2 Hz), 6.01 (1H , s), 6.82 (1H, d, J = 9.9 Hz), 7.01 (1H, d, J = 9.9 Hz), 7.13-7.20 (2H, m), 7.29-7.43 (4H, m), 7.46-7.53 ( 2H, m) Example 118

A mixture of 6- [2-20 (4-fluorophenyl) -6- (iodine methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3 was refluxed for 12 hours. yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (1.43 g) and NaOMe (612 mg) in MeOH (14.3 mL). After removal of solvent, the mixture was extracted with EtOAc, washed with 5% citric acid, and dried over MgSO4. Upon removal of solvent, 6- [2- (4-fluorophenyl) -6-methylene-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2 - ( 2-methylphenyl) pyridazin-3 (2H) -one (1.0 g) as a yellow amorphous solid. Mass ESI (+) 414 (M + 1) 1H-NMR (CDCl3) δ 2.22 (3H, s), 3.90 (2H, s), 4.80 (2H, s), 5.28 (1H, s), 5.33 (1H , s), 5.97 (1H, s), 6.82 (1H, d, J = 10.0 Hz), 7.02 (1H, d, J = 10.4 Hz), 7.14-7.20 (2H, m), 7.31-7.40 (4H, m) 7.50-7.56 (2H, m). Example 119

A mixture of 6- [2- (4-fluorophenyl) -6-methylene-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin -3 (2H) -one (100 mg), 10% palladium on carbon (26 mg), and MeOH (1 mL) was stirred for 5 h in H2 gas until completion of the reaction. The mixture was filtered through Celite® pad and the filtrate was evaporated. The crude residue was purified by column chromatography (eluent: 1% MeOH in CHCl 3) to give 6- [2- (4-fluorophenyl) -6-methyl-4,5,6,7-tetrahydropyrazol [1,5- a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (43.8 mg).

Mass ESI (+) 438 (M + Na)

1H-NMR (CDCl3) δ 1.02 (3H, d), 2.08 (3H, s), 2.21 (1H, brs), 2.88 (1H, t), 3.27 (1H, m), 3.63 (1H, dd), 4.12 (1H, dd), 6.92 (1H, d), 7.08 (1H, d), 7.23 (2H, t), 7.34 (4H, m), 7.47 (2H, dd).

Example 120

A mixture of 6- [2- (4-fluorophenyl) -6-methylene-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazinecarboxylic acid 3 (2H) -one (150 mg), OsO4 (46 mg), Methyl morpholine N-oxide (55.3 mg), H2O (0.6 mL), acetone (0.6 mL), and MeCN (0 , 6 mL) was stirred for 3 weeks and then filtered through Celite® pad. The filtrate was evaporated and the residue was purified by column chromatography to give 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) pyrazol [1,5-a] pyrimidin-3-yl] - 2- (2-methylphenyl) pyridazin-3 (2H) -one (37.0 mg). Mass ESI (+) 450 (M + Na) 1H-NMR (CDCl3) δ 2.14 (3H, s), 4.83 (2H, s), 7.04 (2H, t), 7.14 (3H, m), 7.30 (2H , m), 7.70 (2H, dd), 7.92 (1H, d), 8.58 (1H, s), 8.71 (1H, s)

Example 121

A mixture of 6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [1,3-dioxolane-2,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (500 mg) and conc. NaCl (10 mL) was stirred at 80 ° C overnight. Water (40 mL) and EtOAc (60 mL) were added to the solution, and the biphasic solution was made alkaline with Na 2 CO 3. The aqueous layer was removed, and the organic layer was washed successively with saturated aqueous NaHCO 3 solution (30 mL, 2 times) and brine (20 mL). The organic layer was dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo to give 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5-dihydropyrazol [1, 5-a] pyrimidin-6 (7H) -one (453 mg) as a yellow oil.

Mass ESI (-) 414 (M-I)

1H-NMR (CDCl3) δ 2.21 (3H, s), 3.97 (1H, s), 4.74 (1H, s), 6.08 (1H, brs), 6.86 (1H, d, J = 9.6 Hz), 7.06 (1H , d, J = 9.6 Hz), 7.18 (2H, dd, J = 8.7 Hz, J = 8.7 Hz), 7.32-7.42 (4H, m), 7.51 (2H, dd, J = 8.7 Hz, J = 5.5 Hz)

Example 122

To the solution of 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5-dihydropyrazolo [1,5-a] pyrimidin -6 (7H) -one (453 mg) in EtOH (5 mL) was added a solution of hydroxylamine hydrochloride (94.7 mg) in water (0.35 mL) and stirred for 1.5 h. the solution at room temperature. To the solution was added CHCl 3 (50 mL), and the suspension was washed successively with 10% aqueous citric acid solution (30 mL), saturated aqueous NaHCO 3 solution (30 mL) and brine (30 mL). The organic layer was dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (elution gradient: EtOAc / hexane = 0/1 to 1/0) to give 2- (4-fluorophenyl) -3 - [1 - () oxime. 2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5-dihydropyrazolo [1,5-a] pyrimidin-6 (7H) -one (122 mg, geometric isomer ratio = 1 : 3) as a brown solid.

Mass ESI (+) 431 (M + 1)

1H-NMR (CDCl3) δ 2.23 (3H, s), 4.00 (2H, d, J = 2.0 Hz), 4.28 (0.6H, d, 2.0 Hz), 4.79 (0.6H, s), 5.04 (2H , s), 5.98 (2H, brs), 6.84 (0.3H, d, J = 10 Hz), 6.84 (1H, d, J = 10.0 Hz), 7.03 (0.3H, d, J = 10 .0 Hz), 7.04 (1H, d, J = 10.0 Hz), 7.16 (0.6H, dd, J = 8.5 Hz, J = 8.5 Hz), 7.17 (2H, dd, J = 8.5 Hz, J = 8.5 Hz), 7.32-7.42 (4H, m), 7.51 (2H, dd, J = 9.0 Hz, J = 5.5 Hz), 7.51 (0.6H, dd, J = 9.0 Hz, J = 5.5 Hz ), 7.82 (1H, s), 7.97 (0.3H, s) Example 123

To a solution of 6 - [(5S) -5- ({[tertiary butyl (diphenyl) silyl] oxy} methyl) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazol [1,5-a ] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (450 mg) in THF (4.5 mL) was added an IM solution of tetrabutylammonium fluoride in THF (0, 67 mL) at room temperature. After stirring for 30 min, the mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: 2-5% MeOH in CHCl3). The oil obtained from i-PrOH / hexane was crystallized to give 6- [(5S) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazol [1,5-a ] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (269 mg). Mass ESI (+) 454 (M + Na)

1H-NMR (DMS0-d6) δ 1.75-1.84 (1H, m), 2.05-2.09 (1H, m), 2.11 (3H, s), 3.26-3.33 (1H, m), 3.40 (1H, m), 3.48-3.52 (1H, m), 4.00-4.11 (2H, m), 4.89 (1H, t, 5 Hz), 6.11 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.03 (1H , d, J = 10 Hz), 7.26 (2H, t, J = 9 Hz), 7.31-7.37 (4H, m), 7.49 (2H, dd, J = 9Hz, 5 Hz)

Example 124

To a solution of 6 - [(5R) -5- ({[tertiary butyl (diphenyl) silyl] oxymethyl) -2- (4-fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin -3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (450 mg) in THF (4.5 mL) added 1 M solution of tetrabutylammonium fluoride in THF (0.67 mL) at room temperature. After stirring for 30 min, the mixture was partitioned between EtOAc and H2O. The organic layer was dried over MgSO 4, filtered and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: 2-5% MeOH in CHCl3). The oil obtained from i-PrOH / hexane was crystallized to give 6 - [(5R) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazole [1,5-a ] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (269 mg) Mass ESI (+) 454 (M + Na)

1H-NMR (DMSO-d6) δ 1.71-1.84 (1H, m), 2.05-2.09 (1H, m), 2.11 (3H, s), 3.26-3.33 (1H, m), 3.40 (1H, m), 3.48-3.52 (1H, m), 3.98-4.14 (2H, m), 4.89 (1H, t, 5 Hz), 6.11 (1H, brs), 6.92 (1H, d, J = 10 Hz), 7.03 (1H , d, J = 10 Hz), 7.26 (2H, t, J = 9 Hz), 7.31-7.37 (4H, m), 7.49 (2H, dd, J = 9 Hz, 5 Hz)

Example 125

(I) To a solution of lithium Ν, Ν-bis-trimethylsilyl amide (1.55 mL, 1 M solution in THF) in THF (5 mL) was slowly added a mixture of 6- [2- (4 -fluorophenyl) -2-oxoethyl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (500 mg) and THF (10 mL) below -60 ° C in a dry ice / acetone bath, and The whole mixture was stirred at -78 ° C for 30 min. Cyano-carbonyloxyethane (154 mg) was added to the mixture, and all of it was stirred at -78 ° C for 3 h and then at room temperature for 6.5 h. The reaction mixture was diluted with saturated aqueous NH 4 Cl solution (30 mL) and extracted with EtOAc (50 mL). The organic layer was washed with H 2 O and brine (30 mL), dried over MgSO 4 and evaporated. The residue was purified by column chromatography (eluent: CHCl 3 -MeOH) to give 3- (4-fluorophenyl) -2 - [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] Ethyl 3-oxopropanoate (254 mg) as a light yellow oil.

Mass ESI (-) 393 (M-I)

(II) A mixture of ethyl 3- (4-fluorophenyl) -2- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -3-oxo propanoate obtained from above ( I) (196 mg), hydrazine monohydrochloride (40.0 mg) and DMF (4 mL) were stirred at room temperature for 5h. The reaction mixture was diluted with EtOAc (30 mL), and washed with H2O (20 mL, 3 times) and brine (20 mL). A separated solid was collected in an organic layer to give 6- [3- (4-fluorophenyl) -5-hydroxy-1H-pyrazol-4-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one (19.5 mg) as a colorless powder.

Mass ESI (+) 385 (M + Na) (III) To a mixture of 6- [3- (4-fluorophenyl) -5-hydroxy-1H-pyrazol-4yl] -2- (2-methylphenyl) pyridazine 3 (2H) -one obtained above in (II) (100 mg) and DMF (35 mL) were added K 2 CO 3 (152 mg) and 1,2-dibromoethane (52.3 mg) at room temperature and stirred. the whole mixture at 50 ° C for 8 h. The mixture was diluted with EtOAc (300 mL). The whole mixture was washed with H 2 O (150 mL, 3 times) and brine (50 mL), the organic layer was dried over MgSO 4 and evaporated. The residue was purified by column chromatography (eluent: CHCl 3 -MeOH) to give 6- [6- (4-fluorophenyl) -2,3-dihydropyrazol [5,1-b] [1,3] oxazol-7-yl ] -2- (2-methylphenyl) pyridazin-3 (2H) -one (45 mg) as a light yellow amorphous solid.

Mass ESI (+) 411 (M + Na)

1H-NMR (CDCl3) δ 2.02 (3H, s), 4.39 (2H, t, J = 8 Hz), 5.20 (2H, t, J = 8.2 Hz), 7.05 (1H, d, J = 9.6 Hz), 7.12-7.19 (2H, m), 7.22-7.38 (5H, m), 7.52-7.59 (2H, m)

Example 126

6- [2- (4-Fluorophenyl) -6,7-dihydro-5H-pyrazol [5,1-b] [1,3] oxazin-3-yl] -2- (2-methylphenyl) pyridazin -3 (2H) -one in a similar manner to Example 125.

Mass ESI (+) 425 (M + Na)

1H-NMR (CDCl3) δ 2.13 (3H, s), 2.36 (2H, m), 4.26 (2H, t), 4.42 (2H, t), 6.99 (3H, m), 7.30 (5H, m), 7.52 (2H, m)

Example 127

6- [2- (4-Fluorophenyl) -5,6,7,8-tetrahydropyrazol [5,1-b] [1,3] oxazepin-3-yl] -2- (2-methylphenyl) pyridazin -3 (2H) -one according to a similar manner to that of

Example 125.

Mass ESI (+) 439 (M + Na)

1H-NMR (CDCl3) δ 1.82-1.90 (2H, m), 1.99-2.08 (5H, m), 4.17-4.29 (4H, m), 7.09-7.21 (4H, m), 7.24-7.36 (3H, m ), 7.48-7.56 (3H, m)

Example 128

To a solution of 2- (2-methylphenyl) -6- (2-phenyl pyrazol [1,5-a] pyrazin-3-yl) pyridazin-3 (2H) -one (200 mg) in THF (2 mL) and EtOH (1 mL) was added a solution of NaBH4 in H2O (0.2 mL) at room temperature. After 2 h with stirring, the mixture was heated at 50 ° C for 10 min, then quenched by addition of 1N HCl and adjusted to pH 3.

The whole mixture was stirred for 15 min, basified with saturated aqueous NaHCO 3 and extracted with EtOAc. The organic layer was dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: 5% MeOH in CHCl 3). The obtained oil was treated with 4 N HCl, concentrated and triturated with EtOAc to give 2- (2-methylphenyl) -6- (2-phenyl-4,5,6,7-tetrahydropyrazole [1,5-a] hydrochloride pyrazin-3-yl) pyridazin-3 (2H) -one (137 mg) as a powder.

Mass ESI (+) 384 (M + 1)

1H-NMR (DMS0-de) δ 2. 14 (3H, s), 3.63-3.74 (2H, m), 4.35-4.48 (4H, m), 7.04 (1H, d, J = 9.8 Hz), 7.13 (1H, d, J = 9.8 Hz), 7.26 -7.58 (10H, m), 9.61-9.76 (2H, m).

Example 129

To a 2- (2-methylphenyl) -6- (2-phenyl-4,5,5,7-tetrahydropyrazolo [1,5-a] pyrazin-3-yl) pyridazin-3 (2H) hydrochloride suspension -one (95.0 mg) in CH 2 Cl 2 (1.9 mL) were added acetic anhydride (0.032 mL) and N-ethyl-N, N-diisopropylamine (0.118 mL) successively. After stirring for 2h, the mixture was concentrated in vacuo and partitioned between EtOAc and H2O. The organic layer was washed with brine, dried over Na 2 SO 4, filtered and concentrated. The residue was purified by SiO 2 column chromatography (eluent: 5% MeOH in CHCl 3) and triturated with diisopropyl ether to give 6- (5-acetyl-2-phenyl-4,5,6,7-tetrahydropyrazole [1, 5-a] pyrazin-3-yl) -2- (2-methylphenyl) pyridazin-3 (2H) -one (59 mg) as a powder. Mass ESI (+) 448 (M + Na)

1H-NMR (DMSO-d6) δ 2.02-2.21 (6H, m), 3.90-3.99 (2H, m), 4.11-4.32 (2H, m), 4.68-4.82 (2H, m), 7.01 (1H, d, J = 9.6 Hz), 7.11-7.17 (1H, m), 7.25-7.56 (9H, m)

Example 130A a 2- (2-methylphenyl) -6- (2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-3-yl) pyridazin-3 (2H) hydrochloride solution -one (80.0 mg) and acetone (0.046 mL) in CH 2 Cl 2 (1.6 mL) were added NaBH (OAc) 3 (88.4 mg) at room temperature. After 14 h with stirring, the mixture was quenched with 1N HCl (1 mL) and partitioned between EtOAc and saturated aqueous NaHCO 3. The organic layer was washed with saturated aqueous NaHCO 3 and brine, dried over Na 2 SO 4, filtered and concentrated in vacuo. The residue was purified by SiO 2 column chromatography (eluent: 5% MeOH in CHCl 3). The oil obtained was triturated with diisopropyl ether to give 6- (5-isopropyl-2-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazin-3-yl) -2- (2-methylphenyl ) pyridazin-3 (2H) -one (67 mg) as a powder. Mass ESI (+) 426 (M + 1)

1H-NMR (DMS0-d6) δ 1.02 (6H, d, J = 6.9 Hz), 2.11 (3H, s), 2.88 (1H, q, J = 6.9 Hz), 2.95 (2H, t, J = 5.3 Hz), 3.73 (2H, s), 4.14 (2H, t, J = 5.3 Hz), 6.99 (1H, d, J = 9.9 Hz), 7.16 (1H, d, J = 9.9 Hz), 7.31-7.51 (9H, m).

Example 131

To a suspension of NaH (88 mg, 55% in oil) in THF (4 mL) was added a solution of diethyl phosphono acetate in THF (2 mL) at 0 ° C, and the solution was stirred at 0 ° C. same temperature for 30 minutes. To the solution was added a solution of 2- (4-fluorophenyl) -3- [1- (2-methylphenyl) -6-oxo-1,6-dihydropyridazin-3-yl] -4,5-dihydropyrazol [1, 5-a] pyrimidin-6 (7H) -one (691 mg) in THF (2 mL) at 0 ° C, the solution was stirred at the same temperature for 1 hour. To the reaction mixture was added saturated aqueous NH 4 Cl solution (5 mL), and the solution was extracted with CH 2 Cl 2 (10 mL, 2 times). The extracts were combined, and the solution was washed successively with 10% aqueous citric acid solution (10 mL, 2 times), saturated aqueous NaHCO 3 solution (10 mL) and brine (10 mL). The organic layer was dried over anhydrous MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash silica gel column chromatography (gradient elution: EtOAc / hexane = 0/1 to 1/0) to give {2- (4-fluorophenyl) -3- [1- (2-methylphenyl) Ethyl-6-oxo-1,6-dihydropyridazin-3-yl] -4,5-dihydropyrazol [1,5-a] pyrimidin-6-yl} acetate (311 mg) as a light yellow solid.

Mass ESI (+) 486 (M + 1)

1H-NMR (CDCl3) δ 1.27 (3H, t, J = 7.0 Hz), 2.22 (3H, s), 3.07 (2H, s), 4.16 (2H, q, J = 7.0 Hz), 4.14 (2H, s ), 5.73 (1H, brs), 6.81 (1H, d, J = 10.0 Hz), 6.82 (1H, s), 7.00 (1H, d, J = 10.0 Hz), 7.16 (2H, dd, J = 8.5 Hzi J = 8.5 Hz), 7.30-7.42 (4H, m), 7.50 (2H, dd, J = 5.5 Hz, J = 8.5 Hz)

Example 132

6- [2- (4-fluorophenyl) -6,6-dimethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one in a similar manner to Example 60.

Mass ESI (+) 430 (M + 1)

1H-NMR (DMSO-d6) δ 1.03 (6H, s), 2.09 (3H, s), 2.95 (2H, s), 3.76 (2H, s), 6.09 (1H, br), 6.93 (1H, d, J = 10 Hz), 7.11 (1H, d, J = 10 Hz), 7.23 (2H, t, J = 9 Hz), 7.32-7.38 (4H, m), 7.49 (2H, dd, J = 9 Hz, 5 Hz)

The compounds of the present invention are listed in the following tables. <table> table see original document page 116 </column> </row> <table> <table> table see original document page 117 </column> </row> <table > <table> table see original document page 118 </column> </row> <table> <table> table see original document page 119 </column> </row> <table> <table> table see original document page 120 </column></row><table> <table> table see original document page 121 </column> </row> <table> <table> table see original document page 122 </column> </row> <table > <table> table see original document page 123 </column> </row> <table> <table> table see original document page 124 </column> </row> <table> <table> table see original document page 125 </column></row><table> <table> table see original document page 126 </column> </row> <table> <table> table see original document page 127 </column> </row> <table > <table> table see original document page 128 </column> </row> <table> <table> table see original document page 129 </column> </row> <table> <table> table see original document page 130 </column> </row> <table> <table> table see original document page 131 </column> </row> <table> table see original document page 132 </column> < / row> <table>

Industrial Applicability As mentioned above, the present invention may provide a novel pyridazinone derivative compound and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising said compound as an active ingredient and a pharmaceutically acceptable salt thereof. The pyridazinone derivative compound is useful as an active ingredient of a therapeutic or prophylactic agent for various diseases such as pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, psoriasis, etc. This application is based on patent application No. 60 / 712,825, which was filed in the United States on September 1, 2005, and the contents of which are incorporated herein by reference.

Claims (20)

Pyridazinone derivative, characterized in that it is represented by the following formula (I): wherein R1 is hydrogen, a group consisting of substituted or unselected lower substituted alkyl and substituted or unsubstituted aryl; R 'is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; R3 is lower alkyl; ρ is 0, 1 or --2; and each R4 and R5 are hydrogen or join to form a bond; R6 and R7 join to form a group of the formula: where R8 is hydrogen, X is oxygen or N-R9, where R9 is hydrogen, substituted or unsubstituted lower alkanoyl substituted or unsubstituted or substituted lower alkyl, or R8 and R9 may be joined to form a bond, each me η is 0, 1 or 2, each R and R selected from the group consisting of hydrogen, halogen, hydroxy, formyl, cyano, alkyl substituted or unsubstituted lower amino, substituted or unsubstituted amino, substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted or unsubstituted carbamoyl, carboxy, substituted or unsubstituted lower alkoxycarbonyl and substituted or unsubstituted loxy: each R 11, R 13 and R 14 are selected from the group consisting of hydrogen, halogen, substituted or unsubstituted lower alkyl, carboxy and substituted or unsubstituted lower alkoxycarbonyl; R10 and R11 or R12 and R13 may be joined to form substituted or unsubstituted oxo, hydroxyimino, lower alkylene in which one or more carbon atoms may be substituted by heteroatoms, or substituted or unsubstituted lower alkylidene; R 9 and R 10 may be joined to form lower alkylene or a bond; R11 and R13 or R13 and R14 may join to form a bond; provided that when η = 1 and R10, R11, R12, R13 and R14 are simultaneously hydrogen, R9 will be substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkanoyl or a pharmaceutically acceptable salt thereof. A pyridazinone derivative compound according to claim 1, characterized in that R 1 is substituted or unsubstituted hydrogen or aryl; R2 is substituted or unsubstituted aryl; ρ be 0; each R4 and R5 are hydrogen or join to form a bond; and R6 and R7 join to form a group of the formula: wherein R8 is hydrogen; X is oxygen or N-R 9, wherein R 9 is hydrogen, substituted or unsubstituted lower alkanoyl or substituted or unsubstituted lower alkyl; or R8 and R9 may join to form a bond; each m and η are 0, 1 or 2; each R10 and R12 are selected from the group consisting of hydrogen, halogen, hydroxy, formyl, cyano, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted or unsubstituted carbamoyl, carboxy substituted or unsubstituted lower alkoxycarbonyl and substituted or unsubstituted acyloxy; each R11, R13 and R14 are selected from the group consisting of hydrogen, halogen and substituted or unsubstituted lower alkyl; R10 and R11 or R12 and R13 may be joined to form substituted or unsubstituted oxo, hydroxyimino, lower alkylene in which one or more carbon atoms may be substituted by heteroatoms, or substituted or unsubstituted lower alkylidene; R 9 and R 10 may be joined to form lower alkylene or a bond; R11 and R13 or R13 and R14 may join together to form a bond, provided that when η = 1 and R10, R11, R12, R13 and R14 are simultaneously hydrogen, R9 will be substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkanoyl. or a pharmaceutically acceptable salt thereof. Pyridazinone-derived compound according to claim 2, characterized in that R 1 is hydrogen or C 1-14 aryl optionally substituted by C 1-6 alkyl or C 1-6 alkylaminosulfonyl; R 2 is C 6 -C 10 aryl optionally substituted by 1 to 3 substituents selected from halogen, C 1-6 alkyl and C 1-6 alkoxy; ρ be 0; each R4 and R5 are hydrogen or join to form a bond; and R6 and R7 join to form a group of the formula: wherein R8 is hydrogen; X is oxygen or N-R 9, wherein R 9 is hydrogen, C 1-6 alkyl, optionally substituted by carboxy, hydroxy, C 1-6 alkoxycarbonyl, morpholino, morpholino carbonyl or C 1-6 alkylsulfonyloxy or C 2-7 alkanoyl; or R8 and R9 join to form a bond; each m and η are 0, 1 or 2; R10 is hydrogen or C1-6 alkyl optionally substituted by (C1-4 aryl) C1-6 alkoxy, di (C1-4 aryl) alkylsilyloxy or hydroxy; R11 is hydrogen or C1-6 alkyl; R12 is selected from the group consisting of hydrogen; halogen; hydroxy; carboxy; formyl; cyan; C 1-6 alkyl optionally substituted by hydroxy, hydroxyimino, halogen, C 1-6 alkoxy, C 1-7 alkanoyloxy, amino, mono or di (C 1-6 alkylamino) (wherein one or both of said C 1-6 alkyl are optionally substituted by hydroxy C6-4 aryl or (C3-6 cycloalkyl) carbonyl, C1-6 alkylureide, morpholino, or 4-6 membered cyclic amino optionally substituted by hydroxy, C1-6 alkyl or di (C1-6 alkylamino) ; mono or di (C1-6 alkylamino; 4-6 membered cyclic amino; C1-6 alkoxy optionally substituted by C6-4 aryl; carbamoyl optionally substituted by C3-6 cycloalkyl or hydroxy (C1-6 alkyl) (C 1-6 alkoxy) carbonyl and (C 1-6 alkoxy) carbonyloxy R 13 is hydrogen, or C 1-6 alkyl optionally substituted by hydroxy or C 1-7 alkanoyloxy R 14 is hydrogen R 10 and R 11 may be joined to form alkylene in which one or more carbon atoms may be substituted with heteroatoms, the which are optionally substituted by (C6-14 aryl) C1-6 alkoxycarbonyl or C1-7 alkanoyl); R 12 and R 13 may join to form C 2-6 alkylene in which one or more carbon atoms may be substituted with heteroatoms, which are optionally substituted by C 1-6 alkyl optionally substituted by hydroxy, or C 1-7 alkanoyl optionally substituted by C1-6 alkoxy; C 1-6 alkylidene optionally substituted by hydroxy; oxo; or hydroxyimino; R 9 and R 10 may be joined to form C 2-6 alkylidene or a bond; R11 and R13 may join to form a bond; R13 and R14 may join to form a bond; provided that when η = 1 and R10, R11, R12, R13 and R14 are simultaneously hydrogen, R9 will be substituted or unsubstituted lower alkyl or substituted or unsubstituted lower alkanoyl; or a pharmaceutically acceptable salt thereof. Pyridazinone derivative according to Claim 1, characterized in that R 1 is hydrogen, substituted or unsubstituted lower alkyl and substituted or unsubstituted aryl; R2 is selected from the group consisting of substituted or unsubstituted aryl and substituted or unsubstituted thienyl; R3 is lower alkyl; ρ is 0, 1 or 2; R4 and R5 join to form a bond; and R6 and R7 join to form a group of the formula: wherein R15 is selected from the group consisting of hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino, substituted or unsubstituted lower alkoxy, saturated cyclic amino, substituted or unsubstituted carbamoyl, carboxy and substituted or unsubstituted lower alkoxycarbonyl; R 16 is selected from the group consisting of hydrogen, halogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino, saturated cyclic amino, substituted or unsubstituted lower alkoxy, substituted or unsubstituted carbamoyl, carboxy and substituted or unsubstituted lower alkoxycarbonyl substituted; R17 is selected from the group consisting of hydrogen, halogen and substituted or unsubstituted lower alkyl; or R16 and R17 join to form lower alkylene or lower alkylidene; R is hydrogen or substituted or unsubstituted lower alkyl, provided that when both R16 and R17 are simultaneously hydrogen, R18 will be substituted or unsubstituted lower alkyl; and R19 is substituted or unsubstituted hydrogen or lower alkyl, or pharmaceutically acceptable salt thereof. Pyridazinone derivative according to Claim 4, characterized in that R 1 is hydrogen or substituted or unsubstituted aryl; R2 is substituted or unsubstituted aryl; R5 join together to form a bond; and R6 to form a group of the formula: ρ be 0; R e and R 7 join <formula> formula see original document page 138 </formula> in which R15 is substituted or unsubstituted lower alkyl; R 16 is selected from the group consisting of hydrogen, hydroxy, substituted or unsubstituted lower alkyl, substituted or unsubstituted amino and saturated cyclic amino; R17 is hydrogen; R18 is substituted or unsubstituted lower alkyl or hydrogen; and R19 is substituted or unsubstituted hydrogen or lower alkyl, or pharmaceutically acceptable salt thereof. Pyridazinone derivative according to claim 5, characterized in that R1 is selected from the group consisting of hydrogen and C6-14 aryl optionally substituted by C1-6 alkyl or C1-6 alkylaminosulfonyl; R2 is C6-14 aryl optionally substituted by 1 to 3 substituents selected from halogen, C1-4 alkyl and C1-6 alkoxy; ρ be 0; R4 and R5 join to form a bond; and R6 and R7 join to form a group of the formula: wherein R15 is mono or di (C1-6 alkylamino (C1-6 alkyl) or hydroxy ( C 1-6 alkyl); R16 is selected from the group consisting of hydrogen; hydroxy; C 1-6 alkyl optionally substituted by hydroxy, halogen, methylamino, dimethylamino, (2-hydroxyethyl) methylamino, morpholino or 4- (dimethylamino) -1-piperidinyl; mono or di (C1-6 alkylamino); R17 is hydrogen; R18 is hydrogen or C1-6 alkyl optionally substituted by carboxy, hydroxy, (C1-6 alkoxy) carbonyl, morpholino, morpholino carbonyl or (C1-6 alkyl) sulfonyloxy; and R19 is C1-6 alkyl optionally substituted by carboxy, hydroxy, (C1-6 alkyl) carbonyl, morpholino, morpholino carbonyl, or (C1-6 alkyl) sulfonyloxy, or a pharmaceutically acceptable salt thereof. Pharmaceutical composition, characterized in that it comprises the compound as defined by claim 1 or a pharmaceutically acceptable salt thereof mixed with a pharmaceutically acceptable carrier. Pharmaceutical composition according to claim 7, characterized in that it is for the prevention or treatment of a disease selected from the group consisting of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease and psoriasis. A method for preventing or treating a disease, selected from the group consisting of pain, rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, and psoriasis, comprising administering an effective amount of the compound as defined by the claim. 1 or a pharmaceutically acceptable salt thereof in a mammal in need thereof. Use of a pyridazinone derivative as defined by claim 1 or a pharmaceutically acceptable salt thereof, which is for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease selected from the group consisting of pain. , rheumatoid arthritis, other conditions associated with inflammation, Crohn's disease, inflammatory bowel disease, and psoriasis. 11. A compound characterized in that it is defined by 6- {2- (2,4-difluoro phenyl) -6 - [(dimethylamino) methyl] -4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidin-3-yl} -2- (2-methylphenyl) -3 (2H) -pyridazinone. 12. A compound characterized in that it is defined by 6- [2- (4-fluorophenyl) -6- (hydroxymethyl) -4,5,6,7-tetrahydropyrazol [1,5-a] pyrimidin-3-yl ] -2- (2-methylphenyl) -3 (2H) -pyridazinone. 13. A compound characterized in that it is defined by 6 - [- 2- (4-fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] - 2- (2-methylphenyl) -3 (2H) -pyridazinone. 14. A compound characterized in that it is defined by 6- [2- (2,4-difluoro phenyl) -6- (hydroxy methyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-2-one. 3-yl] -2- (2-methylphenyl) -3 (2H) -pyridazinone. 15. A compound characterized in that it is defined by 6- [2 '- (4-fluorophenyl) -2,3,4', 5,5 ', 6-hexahydrospiro [pyran-4,6'-pyrazol [1, 5-a] pyrimidin-3'-yl] -2- (2-methylphenyl) -pyridazin-3 (2H) -one. 16. A compound characterized in that it is defined by 6- [2 '- (4-fluorophenyl) -4', 5'-dihydrospiro [1,3-dioxolane-2,6'-pyrazol [1,5-a] pyrimidin] -3'-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one 17. A compound characterized in that it is defined as β - [(6R) -2- (4-fluorophenyl) -6-hydroxy-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl ] -2- (2-methylphenyl) pyridazin-3 (2H) -one 18. A compound characterized in that it is defined by 6- [(5S) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-2-one. 3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one. 19. A compound characterized in that it is defined by 6 - [(5R) -2- (4-fluorophenyl) -5- (hydroxymethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-2-one. 3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one. 20. A compound characterized in that it is defined by 6- [2- (4-fluorophenyl) -6,6-dimethyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl] -2- (2-methylphenyl) pyridazin-3 (2H) -one.